Lymphocyte recruitment into the tumor site is altered in patients with MSI-H colon cancer.
ABSTRACT The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.
- SourceAvailable from: Jean-Christophe Sabourin[Show abstract] [Hide abstract]
ABSTRACT: Colorectal cancers (CRCs) with microsatellite instability (MSI) are associated with a good prognosis and a high density of tumor-infiltrating lymphocytes (TILs). We have undertaken to determine the link between TIL densities and MSI CRC histologic features. Using tissue microarrays, T-cell sub-population infiltration, including T cells (CD3), cytotoxic T cells (CD8) and regulatory T cells (FoxP3) were studied in 86 MSI CRCs. We separately analyzed TILs of the stromal and epithelial compartments in the tumor center, the tumoral invasion margin and associated normal tissue. For FoxP3+ TIL density in the tumor center stromal compartment, we found a strong negative correlation with T4 stage (p = 0.01), node invasion (p<0.001) and VELIPI (vascular emboli, lymphatic invasion and perinervous invasion) criteria (p = 0.002). The strong correlation between regulatory T cell density and the absence of VELIPI criteria suggests that this sub-group of T cells is preferentially associated with less invasive tumors.PLoS ONE 04/2013; 8(4):e61001. · 3.53 Impact Factor
- Studies in Surface Science and Catalysis - STUD SURF SCI CATAL. 01/2001; 135:299-299.
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ABSTRACT: PURPOSE: The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations which we previously identified in stage II and III colon cancer. EXPERIMENTAL DESIGN: Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2299 stage II and III colon tumors from NSABP clinical trials C-07 (N=1836) and C-08 (N=463) with Typlex chemistry and Mass Spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). RESULTS: BRAF mutations were associated with MMR deficient tumors (P<0.0001), poor OS (HR=1.46, 95%CI 1.20; 1.79, p≤.0002) and poor SAR (HR=2.31, 95%CI 1.83, 2.95, p<.0001). Mutations in KRAS, NRAS, MET and PIK3CA were not associated with recurrence, OS or SAR. MMR deficient tumors were associated with an improved prognosis based on recurrence (HR=0.48, 95%CI 0.33, 0.70 p<0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. CONCLUSIONS: This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains at least in part previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trial testing new targeted therapies which block relevant signaling pathways. Such clinical trials are under development at NSABP.Clinical Cancer Research 10/2012; · 8.19 Impact Factor