Abstract 317: Colorectal cancers with microsatellite instability harbor an inflammatory microenvironment, different from the one observed in microsatellite stable colorectal cancers

Abstract

Abstract Introduction Most of sporadic or hereditary colorectal cancers (CRC) with microsatellite instability (MSI) have a peculiar histopathologic pattern, notably with a frequent inflammatory lymphocytic component. MSI CRC are associated with a better outcome than microsatellite stable (MSS) CCR, probably in relation with a more effective immune response. The aim of our work was to highlight the inflammatory mechanisms occurring in MSI CRC, by analyzing the cytokines and the in situ immune response encountered in this tumor subtype. Methods A panel of 48 cytokines was measured from 48 MSI CRC and 62 MSS CRC using the bioplex cytokine multiplexed assay (Biorad, Hercules, CA, USA). Immunohistochemistry was performed on a tissue microarray constructed from the same tumors, with the following markers: CD3 (T lymphocytes), CD8 (cytotoxic T lymphocytes), CD45RO (memory T lymphocytes), T-bet (Th1 CD4 cells) and FoxP3 (regulatory T-cells). After immunostaining of each marker, T-cell density was assessed by image analysis. Results Analysis of the 48 cytokines allowed us to assess a higher level of IL1β, IL1-Rα, IL16, Gro-a, IL-8, Ip-10, Mig, Mip-1α, Mip-1β, Rantes and IFN-γ in MSI CRC than in MSS CRC (p<0.001, p=0.049, p=0.011, p=0.033, p<0.001, p<0.001, p<0.001, p=0.032, p=0.022, p<0.001 and p=0.038, respectively). Conversely, Lif et Mif were expressed at a lower level in MSI CRC than in MSS CRC (p=0.031 and p=0.039, respectively). Immunohistochemistry combined with image analysis evidenced a higher density of CD3+, CD8+, CD45RO+ and T-bet+ T lymphocytes in MSI than in MSS CRC (p=0.046, p<0.001, p<0.001, and p<0.001, respectively) whereas the density of Treg cells (FoxP3+) was not statistically different between both tumor sets (p= 0.276). In addition, within the MSS group, no difference of cytokine expression was seen, according to the presence of a lymphocytic inflammatory component. Conclusion The inflammatory component frequently observed in MSI CRC is associated with a cytokine expression profile different from the one observed in MSS CRC. Interestingly, this profile includes Gro-a, IP 10 and Mig cytokines, involved in the T Helper 1 response and the memory CD45RO+ T cells recruitment. Moreover MSS CRC with lymphocytic inflammatory component do not share the same cytokine pattern suggesting an activation of inflammatory pathways specific of MSI CRC. Taken together, these data indicate the major role of adaptative immunity in MSI CRC which may explain the better prognosis of this CRC subtype. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 317. doi:1538-7445.AM2012-317