PBRM1 deficiency enhances PD1 immunotherapeutic sensitivity via chromosomal accessibility in colorectal cancer.

Abstract

Rationale: Tumor cell epigenetics, especially chromosome accessibility, has been reported to be closely related to the tumor immune landscape and immunotherapy. However, the exact mechanism remains unknown. Methods: Whole-exome sequencing was used to analyze 13 colorectal tumor samples treated with PD1 immunotherapy. The assays for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing were used to detect tumor cells' chromosome accessibility status and screen regulatory pathways. Results: Polybromo-1 (PBRM1) was one of the 12 genes with the highest frequency of somatic mutations associated with immunotherapy sensitivity. PBRM1/Pbrm1 deficiency in colorectal cancer promoted PD-1 immunotherapy sensitivity and chemotaxis of CD8⁺ T and NK cells in the microenvironment in vivo and in vitro. ATAC sequencing revealed that deletion of Pbrm1, a critical component of the SWI/SNF complex, increased chromosomal accessibility in tumor cells and triggered the release of cytokines, such as CCL5 and CXCL10, by activating the NF-κB signaling pathway. Application of ACBL1, a PROC inhibitor of PBRM1, in BALB/C mice or colorectal patient-derived tumor organoids (PDTOs) significantly promoted the sensitivity to PD1 antibody immunotherapy. Conclusions: Our study established that PBRM1/Pbrm1 deficiency was positively correlated with PD1 immunotherapeutic sensitivity in colorectal cancer. The underlying molecular mechanisms involved regulation of chromosome accessibility, activation of the NF-κB signaling pathway, and immune cell infiltration in the microenvironment. These findings identify potential molecular targets for enhancing immunotherapy for colorectal cancer.