Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

Abstract

Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8 þ T cells. However, there has yet to be a clear link established between CD8 þ TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3 þ , CD8 þ , and FOXP3 þ TIL densities were quantitated. We found that CD8 þ TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8 þ T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome. Cancer Res; 75(17); 3446-55. Ó2015 AACR.

Extracellular HSP110 skews macrophage polarization in colorectal cancer

“…6 Interestingly, in these good-outcome patients, there was also an increase in the immune cells infiltrating the tumor. 14,[23][24][25][26] In this work, we demonstrated that these two events associated with a good CRC prognosis (i.e., HSP110 expression and tumor immunosurveillance) may be linked. Indeed, we showed that HSP110 is secreted by CRC cells and skews the macrophage inflammatory profile.…”

Multiparametric immune profiling in HPV– oral squamous cell cancer

“…Based on the density, composition, and localization of immune cell infiltrates, in particular of CD8 + T cells, the immunoscore was developed, which had independent prognostic relevance in CRC, in addition to other cancer types (36)(37)(38). In regards to HNSCC, various immune subsets have been correlated with clinical outcome (39,40), but the majority of these reports either focused exclusively on HPV + HNSCC or did not distinguish patient populations based on the HPV status.…”

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4+ T cells

“…The presence of intratumoral T cells is considered a good prognostic factor in colorectal cancer [34][35][36][37][38]. Recent studies indicated that an elevated number of intratumoral T cells, elevated HLA class I expression levels, and STAT1 activation are beneficial prognostic biomarkers for colorectal cancer [39].…”