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.

Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value

“…Another speculative possibility is that BRAF-mutant tumors may have an altered immune response. MMR-deficient tumors have been shown to be associated with a high density of cytotoxic (CD8+) T and memory (CD45RO+) T cells and may be responsible for the good prognosis associated with MMR-deficient tumors (42–44). One of the roles of the activated BRAF/MAPK pathway is immune evasion by the suppression of immunosuppressive factors and inflammatory cytokines, such as interleukin (IL)-10 (45).…”

“…One of the roles of the activated BRAF/MAPK pathway is immune evasion by the suppression of immunosuppressive factors and inflammatory cytokines, such as interleukin (IL)-10 (45). IL-10 has been shown to be required for optimal promotion and sustainment of T-cell memory in a mouse model with IL-10 knockout mice (42, 45). However, if BRAF-mutant tumors have an altered interaction with memory T cell, it is not likely to be the result of a decrease in the density of these cells in the primary tumor because higher density of memory T cells (CD45R0) are also associated with BRAF-mutant tumors (43).…”

Invasive front of colorectal cancer: Dynamic interface ofpro-/anti-tumor factors

“…In addition, a positive correlation between apoptosis rates and higher TIL number has been described, a finding which could perhaps help to explain the improved prognosis seen in patients with MSI-H compared to MSS tumors [98,101] . Studies on T-regs such as FOXP3 and CD25+ have recently been undertaken [102] . Drescher et al [102] , evaluating both MSS and MSI-H cancers found that in contrast to CD8+ T-cells which may be involved in actively preventing growth and/or metastatic in MSI-H tumors, CD25+ cell counts were similar between MSS and MSI-H tumors suggesting no active immunosuppressive mechanisms in MSS cancers.…”

“…Studies on T-regs such as FOXP3 and CD25+ have recently been undertaken [102] . Drescher et al [102] , evaluating both MSS and MSI-H cancers found that in contrast to CD8+ T-cells which may be involved in actively preventing growth and/or metastatic in MSI-H tumors, CD25+ cell counts were similar between MSS and MSI-H tumors suggesting no active immunosuppressive mechanisms in MSS cancers. Finally, the upregulation in MSI-H cancers of a large number of genes involved in immune response and increased levels of pro-inflammatory cytokines and cytotoxic mediators indicate an activated anti-tumor immune response in these tumors [86] .…”

Combined influence of teichoic acids from Staphylococcus aureus and heterometallik Cu/Cd ethylenediamine complex on peritoneal macrophages and tumor cells

“…It should be noted that the increase of rate of lymphocyte infiltration in tumor tissue after mono or combined therapy is one probable mechanism of inhibition of primary tumor (Fig. 3, a) [22][23][24].…”