Effect of TP53 mutation on antitumor immunity and responsiveness to immunotherapy in colorectal cancer.

Abstract

e16014 Background: Although we have approved immune checkpoint inhibitors (ICIs) in microsatellite instability high (MSI-H) or mismatch-repair-deficient (dMMR) colorectal cancer (CRC), more than half of patients did not respond well to ICIs, emphasizing the need for effective biomarkers. Methods: Whole exome sequencing (WES) analysis was performed on a Chinese cohort of MSI-H/dMMR CRC patients (n = 16). We investigated the pertinence between clinic benefit and potential biomarkers, as TP53 mutation and tumor mutational burden (TMB). The open cohort of ICI-treated CRC patients from the Memorial Sloan Kettering cancer center (MSK ICI cohort) further validated the genomic correlation. Besides, we used the colorectal adenocarcinoma (COADREAD) cohort from The Cancer Genome Atlas (TCGA) dataset to explore the effect of TP53 mutation on the genomic and immunogenetic features. Results: In a Chinese cohort of MSI-H/dMMR CRCs receiving ICIs, we found that patients with TP53 mutation (6 out of 16) showed a remarkable lower durable clinic benefit (DCB) rate than TP53 wild-type subgroup (100% vs. 33%, P = 0.008). Moreover, TP53 wild-type patients were associated with prolonged progression-free survival (P = 0.02; HR, 0.11) and overall survival (P = 0.0037; HR, 0.04). However, TMB-high revealed no statistical significant predictive or prognostic value when using top 20%, 40% or 50% as the cutoff values in our cohort. Further, in order to confirm our observation, we analyzed the association of TP53 mutation with clinic outcome in the publicly available MSK ICI-treated CRC cohort. As expected, the TP53 wild-type patients had a better prognosis (P = 0.037; HR, 0.54) versus the TP53 mutant subgroup. Mechanically, we found that the retention of wild-type TP53 in the TCGA COADREAD cohort was associated with improvement of several steps in the cancer immunity cycle. More intriguingly, in the MSI-H subtype, the TP53 wild-type tumors showed enhanced recognition of cancer cells by T cells and a higher proportion of effector memory CD8+ T cells. Finally, TP53 wild-type tumors also showed reduced heterogeneity and decreased burden of copy number variation, but the correlation between TP53 wild-type tumors and TMB was limited due to MSI status. Conclusions: Our study highlights that TP53 mutations in CRC may indicate inhibition of the tumor microenvironment, particularly in MSI-H/dMMR CRCs. Therefore, the assessment of TP53 status may have important significance in predicting the effectiveness of ICIs in CRC patients and their MSI-H /dMMR subgroup.