Background The role of tumor-infiltrating immune cells in theearly metastatic invasion of colorectal cancer is unknown.
Methods We studied pathological signs of early metastatic invasion(venous emboli and lymphatic and perineural invasion) in 959specimens of resected colorectal cancer. The local immune responsewithin the tumor was studied by flow cytometry (39 tumors),low-density-array real-time polymerase-chain-reaction assay(75 tumors), and tissue microarrays (415 tumors).
Results Univariate analysis showed significant differences indisease-free and overall survival according to the presenceor absence of histologic signs of early metastatic invasion(P<0.001). Multivariate Cox analysis showed that an earlyconventional pathological tumor–node–metastasisstage (P<0.001) and the absence of early metastatic invasion(P=0.04) were independently associated with increased survival.As compared with tumors with signs of early metastatic invasion,tumors without such signs had increased infiltrates of immunecells and increased levels of messenger RNA (mRNA) for productsof type 1 helper effector T cells (CD8, T-BET [T-box transcriptionfactor 21], interferon regulatory factor 1, interferon-, granulysin,and granzyme B) but not increased levels of inflammatory mediatorsor immunosuppressive molecules. The two types of tumors hadsignificant differences in the levels of expression of 65 combinationsof T-cell markers, and hierarchical clustering showed that markersof T-cell migration, activation, and differentiation were increasedin tumors without signs of early metastatic invasion. The lattertype of tumors also had increased numbers of CD8+ T cells, rangingfrom early memory (CD45RO+CCR7–CD28+CD27+) to effectormemory (CD45RO+CCR7–CD28–CD27–) T cells. Thepresence of high levels of infiltrating memory CD45RO+ cells,evaluated immunohistochemically, correlated with the absenceof signs of early metastatic invasion, a less advanced pathologicalstage, and increased survival.
Conclusions Signs of an immune response within colorectal cancersare associated with the absence of pathological evidence ofearly metastatic invasion and with prolonged survival.
Accumulating evidence suggests that tumor progression is governednot only by genetic changes intrinsic to cancer cells1 but alsoby epigenetic and environmental factors. Inflammation is alsoa factor, and there is experimental evidence to support theidea that the innate immune system can promote tumor developmentthrough inflammation-dependent mechanisms.2,3 Recently, increasedproduction of inflammatory mediators, including tumor necrosisfactor (TNF-), by stromal cells was found during cancer progressionin mouse models of colorectal cancer.4,5,6 These results areconsistent with the association between an increased numberof inflammatory cells in tumors and tumor progression.7,8,9,10
By contrast, mice that are deficient in one or more componentsof the adaptive immune system have an increased susceptibilityto spontaneous tumors.11,12 Immune surveillance can not onlyeliminate tumors but also select variant tumor cells that resistthe immune-surveillance mechanism, a process called "immunoediting."11,12In humans, the presence of lymphocytes within the tumor canbe a favorable prognostic sign.11,12,13,14,15 The eliminationphase of cancer immunoediting is thought to be a continuousprocess, and local control of metastatic invasion by the immunesystem may be critical for survival.
Little is known about the role of the immune system in the earlysteps of the metastatic processes, which include vascular emboli,lymphatic invasion, and perineural invasion (collectively referredto as "VELIPI"). We aimed to determine whether VELIPI-positivecolorectal cancers are associated with inflammatory or immunosuppressivemediators, or both, and whether the absence of VELIPI is associatedwith an adaptive immune response.
Methods
Patients and Database
The records of 959 patients with colorectal cancer who underwenta primary resection of the tumor at the Laënnec–GeorgesPompidou European Hospital between 1986 and 2004 were reviewed(Table 1). The observation time in this unselected cohort wasthe interval between diagnosis and last contact (death or lastfollow-up). Data were censored at the last follow-up for patientswho had not relapsed and for those who had died. The mean durationof follow-up was 44.5 months. Six patients lost to follow-upwere excluded from the analysis. Histopathological and clinicalfindings were scored according to the tumor–node–metastasis(TNM) staging system of the Union Internationale contre le Cancer16(Table 1 and the Supplementary Appendix, available with thefull text of this article at www.nejm.org). Early metastaticinvasion was defined by the presence of components of VELIPI,alone or in combination. A VELIPI-positive tumor had at leastone of these pathological findings, whereas a VELIPI-negativetumor had none of the three findings. The TNM stage and VELIPIstatus of the tumors were determined from the histopathologicalreports obtained at the time of resection. A secure, Web-baseddatabase, Tumoral MicroEnvironment Database (TME.db, availableon request), with a three-tier architecture was assembled withthe use of Java-2 Enterprise edition software to integrate clinicaldata sets and the results of high-throughput techniques.
Table 1. Disease-free and Overall Survival among 959 Patients with Colorectal Cancer.
Histopathological Analysis
For each patient, all sections of tumor that had been stainedwith hematoxylin and eosin were reassessed in a blinded fashionby two pathologists or two investigators trained to identifythe pathological features of colonic cancer. Each specimen wasexamined for the following: lymphoid infiltrates within thetumor and a lymphoid reaction at the invasive margin (10 to20 fields analyzed per patient). The densities of these immuneinfiltrates were scored independently by the investigators,as weak (score of 1), moderate (score of 2), or strong (scoreof 3) (details are provided in the Supplementary Appendix).
Real-Time Polymerase-Chain-Reaction Assay
For the polymerase chain reaction (PCR), total RNA was extractedfrom 100 randomly selected frozen tumor specimens from the cohortof 959 patients; 75 samples of sufficient quality and quantitywere analyzed for gene expression with the use of quantitativereal-time TaqMan PCR with low-density arrays and a robotic PCRsystem (model 7900, Applied Biosystems) (details are providedin the Supplementary Appendix).
Large-Scale Flow-Cytometric Analysis
Cells were extracted by mechanical dispersion from 39 freshtumor samples. All cells (including tumor cells) were analyzedby flow cytometry. Cells from normal mucosa from a site thatwas distant from the fresh tumor were also analyzed. Cells wereincubated for 30 minutes at 4°C with antibodies againstimmune-cell markers (details are provided in the Supplementary Appendix).Analyses were performed with a four-color fluorescence-activatedcell sorter (FACScalibur, Becton Dickinson) and CellQuest software(Becton Dickinson). Immune subpopulations were measured as apercentage of the total number of all cells and a percentageof the total number of CD3+ cells. Average-linkage hierarchicalclustering was applied, and the results were displayed withthe use of the Genesis program17,18 (software available at www.genome.tugraz.at).
Construction of Tissue Microarrays
Using a tissue-microarray instrument (Beecher Instruments, Alphelys),we removed two representative areas of the tumor (center andinvasive margin, 0.6 mm and 1 mm in diameter, respectively)from paraffin-embedded tissue blocks that had been preparedat the time of resection. Tissue microarrays containing thetissue cores were then cut into 5-µm sections for stainingwith Harris's hematoxylin and immunohistochemical staining.Of the colonic carcinomas that were resected between 1990 and2003, 50 percent (415) were randomly selected for constructionof tissue microarrays. On the basis of the TNM stage and VELIPIpathological findings, the 415 patients with these tumors wererepresentative of the entire cohort.
Immunohistochemistry
After antigen retrieval and quenching of endogenous peroxidaseactivity, sections were incubated for 60 minutes at room temperaturewith monoclonal antibodies against CD45RO and CD3 (Neomarkers).The Envision+ system (enzyme-conjugated polymer backbone coupledto secondary antibodies) and 3,3'-diaminobenzidine chromogenwere applied (Dako). Tissue sections were counterstained withHarris's hematoxylin. Isotype-matched mouse monoclonal antibodieswere used as negative controls. Slides were analyzed with theuse of an image-analysis workstation (Spot Browser, Alphelys).Polychromatic high-resolution spot images (740 by 540 pixels;resolution, 1.181 µm per pixel) were obtained (magnification,x100). Measurements were recorded as the number of positivecells per unit of tissue surface.
Statistical Analysis
Kaplan–Meier curves were used to assess the influenceof pathological signs of early metastatic invasion (VELIPI)on overall and disease-free survival. The significance of variousclinical characteristics was assessed by univariate analysiswith the use of the log-rank test (Table 1). We used a Cox proportional-hazardsmodel to test the simultaneous influence on overall and disease-freesurvival of all covariates found to be significant in the univariateanalysis. The same tests were used to assess the effect of thedensity of CD45RO+ cells (the number of cells per square millimeter)on overall and disease-free survival, alone or together withthe TNM-stage covariates. The analysis-of-variance t-test andthe Wilcoxon–Mann–Whitney test, respectively, werethe parametric and nonparametric tests used to identify markerswith significantly different levels of expression among VELIPI-positiveand VELIPI-negative tumors. The normality of the logarithm ofthe gene-expression levels and of the densities of CD45RO+ cellswas determined with the use of the Shapiro test. The Wilcoxontest was used to assess the significance of the difference inmedian survival across different groups of patients. All testswere two-sided. A P value of less than 0.05 was considered toindicate statistical significance. All P values are reportedwithout adjustments for multiple corrections. All analyses wereperformed with the use of R and StatView, two types of statisticalsoftware.
Results
Early Metastatic Invasion and Clinical Outcome
The prognostic significance of the presence of VELIPI, whichdelineated early metastatic invasion, was investigated by univariateanalysis of data from the 959 patients with colorectal cancer.The presence or absence of VELIPI as well as the TNM stage significantlyinfluenced disease-free and overall survival (P<0.001 forall comparisons) (Table 1).
The five-year disease-free survival rates were 32.4 percentamong patients with VELIPI-negative tumors and 12.1 percentamong patients with VELIPI-positive tumors (Table 1). Therewere also significant differences in the median duration ofdisease-free survival between patients with VELIPI-positivetumors and patients with VELIPI-negative tumors (3.3 monthsvs. 26.9 months, P<0.001) (Table 1). A similar pattern wasfound for overall survival (Table 1). Furthermore, the presenceof more than one sign of early metastatic invasion conferreda worse prognosis than the presence of a single sign (Figure 1and the Supplementary Appendix). Kaplan–Meier curvessuggested longer overall survival (Figure 1) and disease-freesurvival (data not shown) among patients with VELIPI-negativetumors than among patients with VELIPI-positive tumors (P<0.001by the log-rank test). The VELIPI status correlated with theN and M stages (P<0.001 for all comparisons) (data not shown).
Figure 1. Kaplan–Meier Curves for Overall Survival According to the Presence or Absence of Perineural Invasion (Panel A), Vascular Emboli (Panel B), Lymphatic Invasion (Panel C), or Any Sign of Early Metastatic Invasion (Panel D) among 959 Patients with Colorectal Cancer.
Early metastatic invasion was defined by the presence of vascular emboli, lymphatic invasion, and perineural invasion (collectively referred to as VELIPI), alone or in combination. P<0.001 for all comparisons by the log-rank test.
The influence of all significant covariates on survival wassimultaneously tested with the use of a Cox proportional-hazardsmodel. After adjustment for TNM stage, multivariate analysisconfirmed that the absence of VELIPI was significantly and independentlyassociated with a better prognosis (P=0.04 for overall survivaland P=0.01 for disease-free survival). After adjustment forthe Dukes' stage, the absence of VELIPI was independently associatedwith a better prognosis (P=0.007 for overall survival and P=0.002for disease-free survival) (details are provided in the Supplementary Appendix).
Immune-Cell Infiltration, Inflammation, Early Metastatic Invasion, and Prognosis
A total of 377 colorectal tumors were assessed histopathologicallyfor an immune-cell infiltrate within the tumor and in the invasivemargin (details are provided in the Supplementary Appendix).The presence of a strong immune infiltrate (indicated by a scoreof 3) was associated with VELIPI-negative tumors (see the Supplementary Appendix).We used quantitative real-time PCR with a low-densityarray to measure the levels of messenger RNA (mRNA) for inflammatoryand immunosuppressive molecules in 75 colorectal tumors. Nosignificant association between the content of mRNA for inflammatorymediators (interleukin-8, vascular endothelial growth factor,carcinoembryonic-antigen–related cell-adhesion molecule1, matrix metalloproteinase 7, cyclooxygenase 2, and thrombospondin-1)or for immunosuppressive molecules (transforming growth factor [TGF-], interleukin-10, B7-H3, and CD32b) and VELIPI statusor relapse was found (Figure 2 and data not shown).
Figure 2. Expression of Inflammatory Genes, Immunosuppressive Genes, and Genes Related to the Adaptive Immune Response in a Series of 75 Colorectal Cancers, According to the Presence or Absence of Any Sign of Early Metastatic Invasion and Relapse.
Early metastatic invasion was defined by the presence of vascular emboli, lymphatic invasion, and perineural invasion (collectively referred to as VELIPI), alone or in combination. Relative levels of expression of mRNA were adjusted for the level of 18S mRNA for each sample. The levels are represented as mean percentage (+SE) increases as compared with levels in the group of patients with VELIPI-positive tumors who had a relapse, and P values are for the comparison with the reference group. VEGF denotes vascular endothelial growth factor, CEACAM-1 carcinoembryonic-antigen–related cell-adhesion molecule, MMP-7 matrix metalloproteinase 7, TGF- transforming growth factor , T-BET T-box transcription factor 21, and IRF-1 interferon regulatory factor 1.
T cells differentiate into type 1 or type 2 helper T cells (Th1and Th2, respectively) after the expression of T-BET (T-boxtranscription factor 21) or GATA-3, respectively.19 Protectiveimmune responses are mediated by effector memory T cells withthe phenotype CD8+, CD45RO+, CCR7– (negative for CC chemokinereceptor 7), CD62L– (negative for CD62 ligand), perforin+,granulysin+, granzyme B+. Stimulation with an antigen inducesthese cells to exert an immediate effector function20 by releasingcytotoxic mediators.21,22 As shown in Figure 2, levels of CD8,granzyme B, and granulysin were increased in VELIPI-negativetumors and were further increased in such tumors from patientswho had not relapsed, as compared with levels in VELIPI-positivetumors from patients who had relapsed (P<0.05). Moreover,VELIPI-negative tumors from patients who had not relapsed hada significant increase in the Th1 mediators T-BET, interferonregulatory factor 1, and interferon-, as compared with VELIPI-positivetumors from patients who had relapsed (P<0.05). In contrast,levels of the Th2 transcription factor GATA-3 were not increasedin either group of patients (Figure 2).
Phenotypes of Tumor-Infiltrating Immune Cells
We used large-scale flow cytometry to analyze subpopulationsof immune cells from 39 freshly resected colon cancers. To refinethe analysis, 410 combinations of surface markers were measuredby means of flow cytometry, and the results were plotted fromthe minimal (blue) to the maximal (red) level of expression(Figure 3A). T cells, B cells, natural killer cells, naturalkiller T cells, and macrophages were analyzed in relation tothe VELIPI status of the tumors. CD3+ T cells were the mostprevalent tumor-infiltrating immune cells. The levels of CD3+,CD3+CD4+, and CD3+CD8+ T cells were significantly increased(by a factor of 2.6, 2.5, and 4.9, respectively; P<0.05)in VELIPI-negative tumors as compared with VELIPI-positive tumors(see the Supplementary Appendix). Large-scale analysis of phenotypicand functional markers of T-cell subpopulations (percentageof positive cells in the total population isolated from thetumor and within the CD3+ T-cell population) revealed a significantdifference (P<0.05) between VELIPI-negative and VELIPI-positivetumors for 65 different combinations of markers. Hierarchicalclustering23 showed a homogeneous pattern in VELIPI-positivetumors, whereas two subgroups of VELIPI-negative tumors couldbe distinguished (Figure 3B). All markers (CD45RO, CD45RA, CD27,CD28, CCR7, and CD127) of the T-cell differentiation process,from naive to effector memory T cells, were present in the clusterof differentially expressed markers. Markers of T-cell migration(CD62L–, CC chemokine receptor 7 [CCR7–], CD103,CD49d, and CXC chemokine receptor 3 [CXCR3]) and activation(HLA-DR, CD98, CD80, CD86, and CD134) were also differentiallyexpressed between VELIPI-negative and VELIPI-positive tumors.Figure 3C shows that naive T cells (CD3+CCR7+) were rare inthe tumors. By contrast, in the differentiation pathway fromearly memory T cells (CD45RO+CCR7–CD28+CD27+) to effectormemory T cells (CD45RO+CCR7– CD28–CD27–),all subpopulations were detected. As compared with VELIPI-positivetumors, VELIPI-negative tumors had significantly more of theseT cells (P<0.05). Figure 3D shows the high proportion ofmature CD8+ T cells in VELIPI-negative tumors. In contrast totumors, distant normal mucosa from the same patients did nothave significant differences in the CD8+ T-cell subpopulationsaccording to VELIPI status (data not shown).
Figure 3. Large-Scale Four-Color Flow-Cytometric Analysis of the Cell Populations and Immune-Cell Subpopulations in Freshly Resected Tumors from 39 Patients with Colorectal Carcinoma.
Early metastatic invasion was defined by the presence of vascular emboli, lymphatic invasion, and perineural invasion (collectively referred to as VELIPI), alone or in combination. Panel A shows the 410 combinations of surface markers measured by means of a fluorescence-activated cell sorter and subsequently plotted from the minimal level of expression (blue) to the maximal (red); gray areas represent analyses that were not done. Panel B shows the hierarchical clustering of the 65 combinations of markers that differed significantly between VELIPI-negative and VELIPI-positive tumors (P<0.05). Panel C shows the T-cell differentiation process with the use of the markers CD45RO, CCR7, CD28, and CD27. Cells were analyzed in VELIPI-postive tumors and VELIPI-negative tumors and expressed as the mean (+SE) percentage of the total cells present within the tumor. Panel D shows the CD8+ T-cell subpopulations from naive to effector T cells with the use of the markers CD3, CD8, CCR7, and CD45RO, represented as the mean (+SE) percentage of the total cells within the tumor and as the factor increase among VELIPI-negative tumors, as compared with VELIPI-positive tumors. Immune-cell subpopulations (percentage of positive cells in the total population isolated from the tumor and with the CD3+ T-cell population) analyzed as a percentage of total cells reflect their density within the tumor. The Mann–Whitney test was used for statistical analyses.
Effector Memory T Cells and Survival
We performed immunohistochemical analysis of tissue microarraysprepared from 415 colorectal cancers. Staining with an antibodyagainst CD3 revealed the presence of T cells both within andat the invasive margin of the tumor (data not shown). We usedautomatic-image software to count CD45RO+ cells (Figure 4A).A validation study showed a close correlation between opticaland automatic cell counts (R2=0.914, P<0.001) (Figure 4B).
Figure 4. Tissue Microarray (Panel A); Correlation between Optical and Automatic Counts of CD45RO+ Cells (Panel B); Mean (+SE) Density of CD45RO+ Cells According to the Presence or Absence of Early Metastatic Invasion, Nodal (N) Stage, and Metastatis (M) Stage (Panel C); and Overall and Disease-free Survival According to the Presence of a High or Low Density of CD45RO+ Cells within the Tumor (Panel D).
Early metastatic invasion was defined by the presence of vascular emboli, lymphatic invasion, and perineural invasion (collectively referred to as VELIPI), alone or in combination. Panel A shows the tissue microarrays. Four cores were obtained (two from the center and two from the invasive margin of the tumor) from the tumor specimens from 415 patients with colorectal cancer. Panel A shows an enlargement of a spot and an enlargement of CD45RO+ cells, as well as the digital image captured by the camera and analyzed by the image software (Spot Browser), with tissue represented in yellow and CD45RO+ cells represented in red. Panel B shows the correlation between optical and automatic counts of CD45RO+ cells in 100 randomly selected patients. Panel C shows the mean (±SE) numbers of CD45RO+ cells in the various groups of patients according to the VELIPI, N, and M status. N and M stages were determined according to the TNM staging system of the Union Internationale contre le Cancer.16 NA denotes not applicable. The Mann–Whitney test was used for statistical analyses. Panel D shows Kaplan–Meier curves for overall survival and disease-free survival among 160 patients with tumors that had a high density of CD45RO+ cells (at least 250 per square millimeter) and 176 patients with tumors that had a low density of CD45RO+ cells (fewer than 250 per square millimeter).
VELIPI-negative tumors contained high numbers of CD45RO+ cellsas compared with VELIPI-positive tumors (P=0.02). In addition,a high density of memory T cells was associated with tumorswithout lymph-node involvement and metastases (P<0.001).Advanced stages of lymph-node invasion (N2 and N3) were associatedwith low densities of CD45RO+ cells in tumors (Figure 4C). MultivariateCox proportional-hazards analysis showed that the M stage (P<0.001),the N stage (P=0.002), and the T stage (P=0.004) as well asthe CD45RO+ status (P=0.02) were independent prognostic factorsfor overall survival (details are provided in the Supplementary Appendix).Kaplan–Meier curves suggested longer overallsurvival and disease-free survival (Figure 4) among patientswith tumors containing a high density of CD45RO+ cells thanamong patients whose tumors had a low density of such cells(P<0.001 by the log-rank test). Patients whose tumors hada high density of CD45RO+ cells had a median disease-free survivalof 36.5 months and a median overall survival of 53.2 months,as compared with 11.1 months and 20.6 months, respectively,among patients with tumors that had a low density of CD45RO+cells (P<0.001 for all comparisons) (Figure 4D). The respectivefive-year overall and disease-free survival rates were 46.3percent and 43.1 percent among patients with tumors containinga high density of CD45RO+ cells and 23.7 percent and 21.5 percentamong patients with tumors containing a low density of CD45RO+cells (Figure 4D).
Discussion
Our studies demonstrate a relation between the pathologicalsigns of early metastatic invasion —vascular emboli, lymphaticinvasion, and perineural invasion, collectively termed "VELIPI"— and the outcome in 959 colorectal cancers. We also foundan association between the VELIPI status of the tumor and evidenceof an immune response within the tumor. In particular, an analysisof 39 colorectal cancers showed that the presence of effectormemory T cells within the tumor, defined by the presence ofCD3, CD8, CD45RO, CCR7, CD28, and CD27 markers, was associatedwith VELIPI-negative tumors. Analysis of 415 colorectal tumorsshowed that a high density of infiltrating CD45RO+ cells correlatedwith a good clinical outcome.
The influence of early metastatic invasion on the course ofcolorectal cancer has been reported previously, but there aredisparities in the literature, owing to inherent problems inthe histopathological analysis of this phenomenon.24,25 In ourseries of 959 colorectal cancers, emboli detected by routinepathological examination showed a significant, independent associationbetween VELIPI status and overall survival. Nevertheless, cautionis warranted in interpreting these results, because of possiblefalse negative cases. The identification of tumor emboli couldbe improved by the use of immunohistochemical staining of endotheliumor neural structures. Such an approach is not routine.
Some tumors acquire the ability to sabotage inflammatory responsesand exploit them to promote the proliferation, survival, andinvasiveness of tumor cells.2,3,26,27 For this reason, the presenceof leukocytes within a tumor may be a consequence of an inflammatoryresponse that favors either dissemination of tumor cells ora protective host response.
Infiltrates of immune cells were frequent in tumors withoutperineural or lymphovascular emboli but rare in tumors withperineural or lymphovascular emboli, suggesting a beneficialeffect of the host's immune response. We found no significantdifferences in the levels of mRNA for inflammatory and immunosuppressivemolecules between VELIPI-positive and VELIPI-negative tumorsor between tumors from patients who did not have a relapse andtumors from patients who had a relapse. These findings suggestthat inflammation is not a factor in early metastatic invasion.In contrast, there were increased levels of mRNA for productsand markers of Th1 effector T cells (CD8, T-BET, interferonregulatory factor 1, interferon-, granulysin, and granzyme B),and this increase was associated with prolonged survival andthe absence of pathological signs of early metastatic invasion.Previous reports have shown that the presence of lymphocyteswithin the tumor and Th1-related cytokines such as interleukin-18can be favorable prognostic signs.11,28
In mice, protective immunity against colon cancer is mediatedin part by long-lived memory T cells.29 These cells may be responsiblefor long-lasting protection against tumors. In our study ofcolorectal cancers from patients, we showed that, as comparedwith VELIPI-positive tumors, VELIPI-negative tumors containedsignificantly more memory T cells. All stages of T-cell differentiationwere represented in VELIPI-negative tumors, with a pronouncedincrease in mature T cells, suggesting a process of T-cell differentiation.These findings are inconsistent with infiltration of the tumorby inactive, anergic T cells. Using tissue microarrays, we confirmedthe association between a high number of CD45RO+ T cells andthe absence of lymphovascular and perineural invasion (P<0.02).Tumors that had a high density of effector memory T cells wereassociated with longer disease-free and overall survival thantumors without such cells (P<0.001). The presence of CD45RO+memory T cells in the tumor was an independent prognostic factor.
Our use of high-throughput quantitative measurement of cellularand molecular differences among colorectal cancers allowed usto make a detailed characterization of the tumor microenvironmentand to identify associations with clinical outcomes. Our datasuggest that the tumor microenvironment and the host's immuneresponse are of major importance in tumor progression.
Supported by the Association pour la Recherche sur le Cancer(ARC) through the Alliance pour la Recherche sur le Cancer network(ARECA), INSERM, the Austrian Genome Program (BioinformaticsIntegration Project), and the Austrian Academy of Sciences.No other potential conflict of interest relevant to this articlewas reported.
We are indebted to Alphelys (Plaisir, France) for help withtissue-microarray experiments and digital capture and analysis,to Emmanuel Martin and Applied Biosystems France, and LuisaDandolo for their cooperation and technical support with thelow-density-array quantitative real-time PCR experiments, toAurelia Rodi and Sylvain Ladevèze for expert technicalassistance, and to Drs. Ion Gresser and Colin Anderson for criticallyreading the manuscript.
Source Information
From INSERM Unité 255, René Descartes Faculté de Médecine, Assistance Publique–Hôpitaux de Paris, Cordeliers Biomedical Research Center, University Paris 6, Paris (F.P., M.C., A.C., A.K., M.N., W.-H.F., J.G.); the Laboratory of Immunology (F.P., W.-H.F.) and the Departments of General and Digestive Surgery (A.B., P.-H.C.) and Pathology (D.D., T.M., P.B.), Georges Pompidou European Hospital, Paris; and the Institute for Genomics and Bioinformatics, Graz University of Technology, Graz, Austria (F.S.-C., R.M., B.M., Z.T.). Drs. Pagès and Berger contributed equally to the article.
Address reprint requests to Dr. Galon at INSERM U255, 15 rue de l'Ecole de Médecine, Centre de Recherches Biomédicales des Cordeliers, 75006 Paris, France, or at jerome.galon{at}u255.bhdc.jussieu.fr.
References
Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer 2003;3:55-63. [CrossRef][Web of Science][Medline]
Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860-867. [CrossRef][Medline]
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004;4:71-78. [CrossRef][Web of Science][Medline]
Greten FR, Eckmann L, Greten TF, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285-296. [CrossRef][Web of Science][Medline]
Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461-466. [CrossRef][Medline]
Moore RJ, Owens DM, Stamp G, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999;5:828-831. [Erratum, Nat Med 1999;5:1087.] [CrossRef][Web of Science][Medline]
Voronov E, Shouval DS, Krelin Y, et al. IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 2003;100:2645-2650. [Free Full Text]
Enzler T, Gillessen S, Manis JP, et al. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med 2003;197:1213-1219. [Free Full Text]
Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002;3:991-998. [CrossRef][Web of Science][Medline]
Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol 2001;2:293-299. [CrossRef][Web of Science][Medline]
Dalerba P, Maccalli C, Casati C, Castelli C, Parmiani G. Immunology and immunotherapy of colorectal cancer. Crit Rev Oncol Hematol 2003;46:33-57. [Web of Science][Medline]
Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003;348:203-213. [Free Full Text]
Sobin LH, Wittekind C, eds. TNM classification of malignant tumors. 6th ed. New York: Wiley–Liss, 2002.
Sturn A, Quackenbush J, Trajanoski Z. Genesis: cluster analysis of microarray data. Bioinformatics 2002;18:207-208. [Free Full Text]
Galon J, Franchimont D, Hiroi N, et al. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells. FASEB J 2002;16:61-71. [Free Full Text]
Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 2004;22:745-763. [CrossRef][Web of Science][Medline]
Stenger S, Hanson DA, Teitelbaum R, et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 1998;282:121-125. [Free Full Text]
Motyka B, Korbutt G, Pinkoski MJ, et al. Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell 2000;103:491-500. [CrossRef][Web of Science][Medline]
Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 1998;95:14863-14868. [Free Full Text]
Compton C, Fenoglio-Preiser CM, Pettigrew N, Fielding LP. American Joint Committee on Cancer Prognostic Factors Consensus Conference: Colorectal Working Group. Cancer 2000;88:1739-1757. [CrossRef][Web of Science][Medline]
Compton CC. Colorectal carcinoma: diagnostic, prognostic, and molecular features. Mod Pathol 2003;16:376-388. [CrossRef][Medline]
Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-379. [CrossRef][Medline]
Pages F, Berger A, Henglein B, et al. Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance. Int J Cancer 1999;84:326-330. [CrossRef][Medline]
Xiang R, Lode HN, Gillies SD, Reisfeld RA. T cell memory against colon carcinoma is long-lived in the absence of antigen. J Immunol 1999;163:3676-3683. [Free Full Text]
Solinas, G., Germano, G., Mantovani, A., Allavena, P.
(2009). Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J. Leukoc. Biol.
86: 1065-1073
[Abstract][Full Text]
Attig, S., Hennenlotter, J., Pawelec, G., Klein, G., Koch, S. D., Pircher, H., Feyerabend, S., Wernet, D., Stenzl, A., Rammensee, H.-G., Gouttefangeas, C.
(2009). Simultaneous Infiltration of Polyfunctional Effector and Suppressor T Cells into Renal Cell Carcinomas. Cancer Res.
69: 8412-8419
[Abstract][Full Text]
Ogino, S., Nosho, K., Irahara, N., Meyerhardt, J. A., Baba, Y., Shima, K., Glickman, J. N., Ferrone, C. R., Mino-Kenudson, M., Tanaka, N., Dranoff, G., Giovannucci, E. L., Fuchs, C. S.
(2009). Lymphocytic Reaction to Colorectal Cancer Is Associated with Longer Survival, Independent of Lymph Node Count, Microsatellite Instability, and CpG Island Methylator Phenotype. Clin. Cancer Res.
15: 6412-6420
[Abstract][Full Text]
Brignone, C., Escudier, B., Grygar, C., Marcu, M., Triebel, F.
(2009). A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma. Clin. Cancer Res.
15: 6225-6231
[Abstract][Full Text]
Schetter, A. J., Nguyen, G. H., Bowman, E. D., Mathe, E. A., Yuen, S. T., Hawkes, J. E., Croce, C. M., Leung, S. Y., Harris, C. C.
(2009). Association of Inflammation-Related and microRNA Gene Expression with Cancer-Specific Mortality of Colon Adenocarcinoma. Clin. Cancer Res.
15: 5878-5887
[Abstract][Full Text]
Warren, E. H
(2009). Genetic risk for colitis-associated colorectal cancer. Gut
58: 1177-1179
[Full Text]
Alexe, G., Monaco, J., Doyle, S., Basavanhally, A., Reddy, A., Seiler, M., Ganesan, S., Bhanot, G., Madabhushi, A.
(2009). Towards Improved Cancer Diagnosis and Prognosis Using Analysis of Gene Expression Data and Computer Aided Imaging. Exp. Biol. Med.
234: 860-879
[Abstract][Full Text]
Chaput, N, Louafi, S, Bardier, A, Charlotte, F, Vaillant, J-C, Menegaux, F, Rosenzwajg, M, Lemoine, F, Klatzmann, D, Taieb, J
(2009). Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue. Gut
58: 520-529
[Abstract][Full Text]
Camus, M., Tosolini, M., Mlecnik, B., Pages, F., Kirilovsky, A., Berger, A., Costes, A., Bindea, G., Charoentong, P., Bruneval, P., Trajanoski, Z., Fridman, W.-H., Galon, J.
(2009). Coordination of Intratumoral Immune Reaction and Human Colorectal Cancer Recurrence. Cancer Res.
69: 2685-2693
[Abstract][Full Text]
Jursik, C., Prchal, M., Grillari-Voglauer, R., Drbal, K., Fuertbauer, E., Jungfer, H., Albert, W. H., Steinhuber, E., Hemetsberger, T., Grillari, J., Stockinger, H., Katinger, H.
(2009). Large-Scale Production and Characterization of Novel CD4+ Cytotoxic T Cells with Broad Tumor Specificity for Immunotherapy. Mol Cancer Res
7: 339-353
[Abstract][Full Text]
Ruby, C. E., Weinberg, A. D.
(2009). OX40-Enhanced Tumor Rejection and Effector T Cell Differentiation Decreases with Age. J. Immunol.
182: 1481-1489
[Abstract][Full Text]
Salama, P., Phillips, M., Grieu, F., Morris, M., Zeps, N., Joseph, D., Platell, C., Iacopetta, B.
(2009). Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer. JCO
27: 186-192
[Abstract][Full Text]
Ribas, A., Comin-Anduix, B., Economou, J. S., Donahue, T. R., de la Rocha, P., Morris, L. F., Jalil, J., Dissette, V. B., Shintaku, I. P., Glaspy, J. A., Gomez-Navarro, J., Cochran, A. J.
(2009). Intratumoral Immune Cell Infiltrates, FoxP3, and Indoleamine 2,3-Dioxygenase in Patients with Melanoma Undergoing CTLA4 Blockade. Clin. Cancer Res.
15: 390-399
[Abstract][Full Text]
Brody, J. D., Goldstein, M. J., Czerwinski, D. K., Levy, R.
(2009). Immunotransplantation preferentially expands T-effector cells over T-regulatory cells and cures large lymphoma tumors. Blood
113: 85-94
[Abstract][Full Text]
Aloulou, N., Bastuji-Garin, S., Le Gouvello, S., Abolhassani, M., Chaumette, M. T., Charachon, A., Leroy, K., Sobhani, I.
(2008). Involvement of the Leptin Receptor in the Immune Response in Intestinal Cancer. Cancer Res.
68: 9413-9422
[Abstract][Full Text]
Abolhassani, M., Aloulou, N., Chaumette, M. T., Aparicio, T., Martin-Garcia, N., Mansour, H., Le Gouvello, S., Delchier, J. C., Sobhani, I.
(2008). Leptin Receptor-Related Immune Response in Colorectal Tumors: The Role of Colonocytes and Interleukin-8. Cancer Res.
68: 9423-9432
[Abstract][Full Text]
Umansky, V., Abschuetz, O., Osen, W., Ramacher, M., Zhao, F., Kato, M., Schadendorf, D.
(2008). Melanoma-Specific Memory T Cells Are Functionally Active in Ret Transgenic Mice without Macroscopic Tumors. Cancer Res.
68: 9451-9458
[Abstract][Full Text]
Maccalli, C., Di Cristanziano, V., Fodale, V., Corsi, D., D'Agostino, G., Petrangeli, V., Laurenti, L., Guida, S., Mazzocchi, A., Arienti, F., Perrone, M. P., Castelli, C., Rivoltini, L., Zagonel, V., Tartaglia, M., Parmiani, G., Belardelli, F.
(2008). Induction of Both CD8+ and CD4+ T-Cell-Mediated Responses in Colorectal Cancer Patients by Colon Antigen-1. Clin. Cancer Res.
14: 7292-7303
[Abstract][Full Text]
Marchesi, F., Piemonti, L., Fedele, G., Destro, A., Roncalli, M., Albarello, L., Doglioni, C., Anselmo, A., Doni, A., Bianchi, P., Laghi, L., Malesci, A., Cervo, L., Malosio, M., Reni, M., Zerbi, A., Di Carlo, V., Mantovani, A., Allavena, P.
(2008). The Chemokine Receptor CX3CR1 Is Involved in the Neural Tropism and Malignant Behavior of Pancreatic Ductal Adenocarcinoma. Cancer Res.
68: 9060-9069
[Abstract][Full Text]
Pages, F., Galon, J., Fridman, W. H.
(2008). The essential role of the in situ immune reaction in human colorectal cancer. J. Leukoc. Biol.
84: 981-987
[Abstract][Full Text]
Dieu-Nosjean, M.-C., Antoine, M., Danel, C., Heudes, D., Wislez, M., Poulot, V., Rabbe, N., Laurans, L., Tartour, E., de Chaisemartin, L., Lebecque, S., Fridman, W.-H., Cadranel, J.
(2008). Long-Term Survival for Patients With Non-Small-Cell Lung Cancer With Intratumoral Lymphoid Structures. JCO
26: 4410-4417
[Abstract][Full Text]
Janson, P. C. J., Marits, P., Thorn, M., Ohlsson, R., Winqvist, O.
(2008). CpG Methylation of the IFNG Gene as a Mechanism to Induce Immunosupression in Tumor-Infiltrating Lymphocytes. J. Immunol.
181: 2878-2886
[Abstract][Full Text]
Menard, C., Ghiringhelli, F., Roux, S., Chaput, N., Mateus, C., Grohmann, U., Caillat-Zucman, S., Zitvogel, L., Robert, C.
(2008). CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?. Clin. Cancer Res.
14: 5242-5249
[Abstract][Full Text]
Dulphy, N., Haas, P., Busson, M., Belhadj, S., Peffault de Latour, R., Robin, M., Carmagnat, M., Loiseau, P., Tamouza, R., Scieux, C., Rabian, C., Di Santo, J. P., Charron, D., Janin, A., Socie, G., Toubert, A.
(2008). An Unusual CD56brightCD16low NK Cell Subset Dominates the Early Posttransplant Period following HLA-Matched Hematopoietic Stem Cell Transplantation. J. Immunol.
181: 2227-2237
[Abstract][Full Text]
Loddenkemper, C., Nagorsen, D., Zeitz, M.
(2008). Foxp3 and microsatellite stability phenotype in colorectal cancer. Gut
57: 725-726
[Full Text]
Le Gouvello, S, Bastuji-Garin, S, Aloulou, N, Mansour, H, Chaumette, M-T, Berrehar, F, Seikour, A, Charachon, A, Karoui, M, Leroy, K, Farcet, J-P, Sobhani, I
(2008). High prevalence of Foxp3 and IL17 in MMR-proficient colorectal carcinomas. Gut
57: 772-779
[Abstract][Full Text]
Han, L. Y., Fletcher, M. S., Urbauer, D. L., Mueller, P., Landen, C. N., Kamat, A. A., Lin, Y. G., Merritt, W. M., Spannuth, W. A., Deavers, M. T., De Geest, K., Gershenson, D. M., Lutgendorf, S. K., Ferrone, S., Sood, A. K.
(2008). HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma. Clin. Cancer Res.
14: 3372-3379
[Abstract][Full Text]
Ladoire, S., Arnould, L., Apetoh, L., Coudert, B., Martin, F., Chauffert, B., Fumoleau, P., Ghiringhelli, F.
(2008). Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3+ Regulatory T Cells. Clin. Cancer Res.
14: 2413-2420
[Abstract][Full Text]
Worschech, A., Kmieciak, M., Knutson, K. L., Bear, H. D., Szalay, A. A., Wang, E., Marincola, F. M., Manjili, M. H.
(2008). Signatures Associated with Rejection or Recurrence in HER-2/neu-Positive Mammary Tumors. Cancer Res.
68: 2436-2446
[Abstract][Full Text]
Morris, M., Platell, C., Iacopetta, B.
(2008). Tumor-Infiltrating Lymphocytes and Perforation in Colon Cancer Predict Positive Response to 5-Fluorouracil Chemotherapy. Clin. Cancer Res.
14: 1413-1417
[Abstract][Full Text]
de Bruin, E. C., van de Velde, C. J.H., van Krieken, J. H. J.M., Marijnen, C. A.M., Medema, J. P.
(2008). Epithelial Human Leukocyte Antigen-DR Expression Predicts Reduced Recurrence Rates and Prolonged Survival in Rectal Cancer Patients. Clin. Cancer Res.
14: 1073-1079
[Abstract][Full Text]
Montes, C. L., Chapoval, A. I., Nelson, J., Orhue, V., Zhang, X., Schulze, D. H., Strome, S. E., Gastman, B. R.
(2008). Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion. Cancer Res.
68: 870-879
[Abstract][Full Text]
Stearman, R. S., Dwyer-Nield, L., Grady, M. C., Malkinson, A. M., Geraci, M. W.
(2008). A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment. Cancer Res.
68: 34-43
[Abstract][Full Text]
Alexe, G., Dalgin, G. S., Scanfeld, D., Tamayo, P., Mesirov, J. P., DeLisi, C., Harris, L., Barnard, N., Martel, M., Levine, A. J., Ganesan, S., Bhanot, G.
(2007). High Expression of Lymphocyte-Associated Genes in Node-Negative HER2+ Breast Cancers Correlates with Lower Recurrence Rates. Cancer Res.
67: 10669-10676
[Abstract][Full Text]
Chang, K.-C., Huang, G.-C., Jones, D., Lin, Y.-H.
(2007). Distribution Patterns of Dendritic Cells and T Cells in Diffuse Large B-Cell Lymphomas Correlate with Prognoses. Clin. Cancer Res.
13: 6666-6672
[Abstract][Full Text]
Wong, S. L., Ji, H., Hollenbeck, B. K., Morris, A. M., Baser, O., Birkmeyer, J. D.
(2007). Hospital Lymph Node Examination Rates and Survival After Resection for Colon Cancer. JAMA
298: 2149-2154
[Abstract][Full Text]
Atreya, I., Schimanski, C. C, Becker, C., Wirtz, S., Dornhoff, H., Schnurer, E., Berger, M. R, Galle, P. R, Herr, W., Neurath, M. F
(2007). The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut
56: 1572-1578
[Abstract][Full Text]
Filaci, G., Fenoglio, D., Fravega, M., Ansaldo, G., Borgonovo, G., Traverso, P., Villaggio, B., Ferrera, A., Kunkl, A., Rizzi, M., Ferrera, F., Balestra, P., Ghio, M., Contini, P., Setti, M., Olive, D., Azzarone, B., Carmignani, G., Ravetti, J. L., Torre, G., Indiveri, F.
(2007). CD8+CD28 T Regulatory Lymphocytes Inhibiting T Cell Proliferative and Cytotoxic Functions Infiltrate Human Cancers. J. Immunol.
179: 4323-4334
[Abstract][Full Text]
Webster, W. S., Thompson, R. H., Harris, K. J., Frigola, X., Kuntz, S., Inman, B. A., Dong, H.
(2007). Targeting Molecular and Cellular Inhibitory Mechanisms for Improvement of Antitumor Memory Responses Reactivated by Tumor Cell Vaccine. J. Immunol.
179: 2860-2869
[Abstract][Full Text]
Dieli, F., Vermijlen, D., Fulfaro, F., Caccamo, N., Meraviglia, S., Cicero, G., Roberts, A., Buccheri, S., D'Asaro, M., Gebbia, N., Salerno, A., Eberl, M., Hayday, A. C.
(2007). Targeting Human {gamma}{delta} T Cells with Zoledronate and Interleukin-2 for Immunotherapy of Hormone-Refractory Prostate Cancer. Cancer Res.
67: 7450-7457
[Abstract][Full Text]
Touitou, V., Daussy, C., Bodaghi, B., Camelo, S., de Kozak, Y., Lehoang, P., Naud, M.-C., Varin, A., Thillaye-Goldenberg, B., Merle-Beral, H., Fridman, W. H., Sautes-Fridman, C., Fisson, S.
(2007). Impaired Th1/Tc1 Cytokine Production of Tumor-Infiltrating Lymphocytes in a Model of Primary Intraocular B-Cell Lymphoma. IOVS
48: 3223-3229
[Abstract][Full Text]
Zipin-Roitman, A., Meshel, T., Sagi-Assif, O., Shalmon, B., Avivi, C., Pfeffer, R. M., Witz, I. P., Ben-Baruch, A.
(2007). CXCL10 Promotes Invasion-Related Properties in Human Colorectal Carcinoma Cells. Cancer Res.
67: 3396-3405
[Abstract][Full Text]
Taylor, R. C., Patel, A., Panageas, K. S., Busam, K. J., Brady, M. S.
(2007). Tumor-Infiltrating Lymphocytes Predict Sentinel Lymph Node Positivity in Patients With Cutaneous Melanoma. JCO
25: 869-875
[Abstract][Full Text]
Galon, J., Fridman, W.-H., Pages, F.
(2007). The Adaptive Immunologic Microenvironment in Colorectal Cancer: A Novel Perspective. Cancer Res.
67: 1883-1886
[Abstract][Full Text]
Perrot, I., Blanchard, D., Freymond, N., Isaac, S., Guibert, B., Pacheco, Y., Lebecque, S.
(2007). Dendritic Cells Infiltrating Human Non-Small Cell Lung Cancer Are Blocked at Immature Stage. J. Immunol.
178: 2763-2769
[Abstract][Full Text]
Ling, K.-L., Dulphy, N., Bahl, P., Salio, M., Maskell, K., Piris, J., Warren, B. F., George, B. D., Mortensen, N. J., Cerundolo, V.
(2007). Modulation of CD103 Expression on Human Colon Carcinoma-Specific CTL. J. Immunol.
178: 2908-2915
[Abstract][Full Text]
Lin, Y.-H., Friederichs, J., Black, M. A., Mages, J., Rosenberg, R., Guilford, P. J., Phillips, V., Thompson-Fawcett, M., Kasabov, N., Toro, T., Merrie, A. E., van Rij, A., Yoon, H.-S., McCall, J. L., Siewert, J. R., Holzmann, B., Reeve, A. E.
(2007). Multiple Gene Expression Classifiers from Different Array Platforms Predict Poor Prognosis of Colorectal Cancer. Clin. Cancer Res.
13: 498-507
[Abstract][Full Text]
Huang, L. P., Lyu, S.-C., Clayberger, C., Krensky, A. M.
(2007). Granulysin-Mediated Tumor Rejection in Transgenic Mice. J. Immunol.
178: 77-84
[Abstract][Full Text]
Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M., Camus, M., Berger, A., Wind, P., Zinzindohoue, F., Bruneval, P., Cugnenc, P.-H., Trajanoski, Z., Fridman, W.-H., Pages, F.
(2006). Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.. Science
313: 1960-1964
[Abstract][Full Text]
Chaput, N., Flament, C., Viaud, S., Taieb, J., Roux, S., Spatz, A., Andre, F., LePecq, J.-B., Boussac, M., Garin, J., Amigorena, S., Thery, C., Zitvogel, L.
(2006). Dendritic cell derived-exosomes: biology and clinical implementations. J. Leukoc. Biol.
80: 471-478
[Abstract][Full Text]
Bini, E. J., Park, J., Francois, F.
(2006). Use of Flexible Sigmoidoscopy to Screen for Colorectal Cancer in HIV-Infected Patients 50 Years of Age and Older.. Arch Intern Med
166: 1626-1631
[Abstract][Full Text]
Johnson, P. M., Porter, G. A., Ricciardi, R., Baxter, N. N.
(2006). Increasing Negative Lymph Node Count Is Independently Associated With Improved Long-Term Survival in Stage IIIB and IIIC Colon Cancer. JCO
24: 3570-3575
[Abstract][Full Text]
Bui, J. D., Uppaluri, R., Hsieh, C.-S., Schreiber, R. D.
(2006). Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins.. Cancer Res.
66: 7301-7309
[Abstract][Full Text]
Hegmans, J. P. J. J., Hemmes, A., Hammad, H., Boon, L., Hoogsteden, H. C., Lambrecht, B. N.
(2006). Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J
27: 1086-1095
[Abstract][Full Text]
Kaufman, H. L., Wolchok, J. D.
(2006). Is Tumor Immunity the Same Thing As Autoimmunity? Implications for Cancer Immunotherapy. JCO
24: 2230-2232
[Full Text]
Wolf, D., Marth, C., Wolf, A. M., Pages, F., Galon, J.
(2006). Immune Cells in Colorectal Cancer. NEJM
354: 1531-1532
[Full Text]
Abramson, J. S.
(2006). T-cell/histiocyte-rich B-cell lymphoma: biology, diagnosis, and management.. The Oncologist
11: 384-392
[Abstract][Full Text]
(2006). Inflammatory Response in Colorectal Cancer Is a Good Prognostic Sign. JWatch Gastroenterology
2006: 3-3
[Full Text]
, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7–CD28+CD27+) to effector memory (CD45RO+CCR7–CD28–CD27–) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. 
(TNF-
[TGF-
Previous
