Abstract 1190: The enrichment of CD8+ T cell in TP53 pathway wild-type microsatellite stable colorectal cancer
Authors: Cai Yi , Zhao Feilong , Zhao Xiaochen , Bai Yuezong 
Published: July 2021

Background: Colorectal cancer (CRC) patients with microsatellite instability-high (MSI-H) may respond to immune checkpoint inhibition (ICI), whereas CRC patients with microsatellite-stable (MSS) have not demonstrated response. However, a proportion of MSS tumors with increased immunogenicity may benefit from ICI therapy. We aim to identify these patients by analyzing the correlation between the three major pathways variation status and immune cell infiltration levels in CRC.

Methods: Tumor tissues from 59 CRC patients were collected. Tumor immune microenvironment (TIME) was evaluated by multiple fluorescent immunohistochemical staining, somatic variations and microsatellite status were tested by next-generation sequencing (NGS). TIME includes antibodies of CD8+T cells, tumor associated macrophage M1/M2, and CD56bright and CD56dim NK cells. TP53, RTK-RAS, and WNT pathways were defined as mutation if mutations were tested in any genes in the corresponding pathway. Notably, TP53 pathway was composed of TP53 and ATM. The validation cohort was comprised of 266 Stage-III/IV TCGA-CRC patients whose immune cell infiltration levels were estimated by xCell (https://xcell.ucsf.edu/).

Results: The 59 CRC patients were classified into two groups: MSI-H (n=11) and MSS(n=48), while the latter was further classified into TP53 mutant (n=44) and TP53 wild-type (n=4) groups according to TP53 pathway mutation status. The infiltration level of CD8+T cells were significantly lower in TP53 mutant MSS group than that of TP53 wild-type MSS (p value: 0.03) and MSI-H groups (p value: 0.01). Median CD8+T cells counts in TP53 mutant MSS, TP53 wild-type MSS, and MSI-H, groups were 87, 293, and 271 per square millimeter. While the infiltration level of tumor associated macrophage M1/M2, CD56bright and CD56dim NK cells were similar among the three groups. Besides, no significant difference of any immune cells was detected between RTK-RAS pathway mutant and wild-type MSS patients, and between WNT pathway mutant and wild-type MSS patients. The higher infiltration of CD8+T cells in TP53 wild-type MSS patients was further validated in TCGA-CRC cohort. Though no significant difference of CD8+T cells density was observed between TP53 wild-type MSS and TP53 mutant MSS in overall cohort, in those whose tumor located on the right colon (n=58), the infiltration level of central memory CD8+T cells (CD8+Tcm) was significantly lower in TP53 mutant MSS group (n=22) than that in MSI-H group (n=12, p=0.04), and there was a trend towards lower CD8+Tcm infiltration in TP53 mutant MSS group than that in TP53 wild-type MSS group (n=11, p=0.06).

Conclusion: The infiltration level of CD8+ T cell in TP53 pathway wild-type MSS CRC patients was significantly higher than that in TP53 pathway mutant MSS CRC, and was comparable to that in MSI-H CRC, which implies the potential benefit of these patients from immune checkpoint inhibitor therapy.

Citation Format: Yi Cai, Feilong Zhao, Xiaochen Zhao, Yuezong Bai. The enrichment of CD8+ T cell in TP53 pathway wild-type microsatellite stable colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1190.