Abstract 1382: Comparison of intratumoral T-cell repertoires in DNA mismatch repair proficient and deficient colon adenocarcinoma

Abstract

Abstract Colon tumors with deficient DNA mismatch repair (dMMR) are infiltrated more densely by T cells than tumors with proficient mismatch repair (pMMR). However, high tumor-infiltrating lymphocytes (TIL) are found in a subset of pMMR tumors and low TIL are seen in a subset of dMMR colon cancer. In this study, we compared T-cell repertoires in 20 pMMR and 27 dMMR colon tumors with high and low TIL counts. CDR3 regions of the TCR beta chain were sequenced by ImmunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). The fraction T cells was calculated by normalizing TCR beta template counts to the total DNA. Sample richness was calculated as the number of unique productive rearrangements in a sample after computationally down-sampling to a common number of T cells to control for variation in sample depth. Simpson clonality was computed as a measure of how evenly productive rearrangements are distributed amongst the total number of T cells. Statistical analyses were performed using Prism 8.0 (GraphPad, La Jolla, CA). The mean TIL counts per high power field (HPF) for TIL-high and TIL-low dMMR tumors were 17.4 (range, 5-37) and 1.8 (range, 0-4). In pMMR tumors, they were 12.8 (range, 6-37) for TIL-high and 0.3 (range, 0-1) for TIL-low groups. The number of T cells measured by TCR sequencing correlated positively with the TIL count (Spearman rho = 0.391; P = 0.007). When comparing by MMR status, we found that dMMR tumors exhibited a trend towards higher Simpson clonality index (P = 0.09), with significantly lower repertoire richness compared to pMMR tumors (P = 0.030). Within dMMR tumors, TIL-high dMMR tumors had higher density (P = 0.017), higher clonality (P = 0.003), and a less rich repertoire (P = 0.003) compared to TIL-low dMMR tumors. Within pMMR tumors, while the T cell density was higher in the TIL-high tumors, we did not observe differences in T cell clonality or repertoire richness between TIL-high vs TIL-low pMMR tumors. Our study found that T cells in dMMR tumors are more clonal and their repertoire is less rich compared with T cells in pMMR tumors. In the dMMR group, T cells in TIL-high tumors were more clonal and their repertoire was less rich compared with T cells in TIL-low tumors, but in the pMMR group, T-cell diversity in TIL-high tumors was comparable to T-cell diversity in TIL-low tumors. These findings suggest that T cells clonally expand in dMMR tumors, possibly in response to MMR deficiency-induced tumor neoantigens. Citation Format: Jin K. Kim, Chin-Tung Chen, Asama Khan, Neil Segal, Zsofia Stadler, Jinru Shia, Vinod P. Balachandran. Comparison of intratumoral T-cell repertoires in DNA mismatch repair proficient and deficient colon adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1382.