Abstract 1605: CERBBP mutation promotes antitumor immunity and as predictive biomarkers for immune checkpoint therapy in colorectal cancer
Authors: Youen Lin, Jiewei Zheng, Tingting Chen, Wenzhuan Xie, Mengli Huang
Journal: Cancer Research (2021)

Abstract Background: The prognosis of colorectal cancer (CRC) remains unsatisfactory, only few CRC patients can benefit from immune checkpoint inhibitors (ICIs) treatment. Tumor immune microenvironment (TME), the Tumor mutation burden (TMB) and PD-L1 expression of ICIs have been confirmed to be promising predictive biomarkers of ICIs in pan-cancer. The roles of CREBBP gene in CRC have not been reported before, and the mutation correlation with ICIs predictive biomarkers and immune response remain unknown. Methods: Whole exome sequencing data of 526 CRC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS) was performed on FFPE tumor samples from 2198 Chinese CRC patients (Chinese cohort). NGS data and clinical data of 110 advanced CRC patients treated with ICIs were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). The tumor-related immune cells infiltration level difference between mutant and wild-type tumors were inferred using TIMER2.0. Tumor mutation burden (TMB) examined by 387/733 gene panel (3D-Med) sequencing. PD-L1 expression was determined by immunohistochemistry (IHC) staining assay using SP263. Survival analysis was determined by Kaplan-Meier (KM) analysis. Results: In total, 8.62% (43/526) of CRC patients in TCGA harboring CREBBP mutation and 2.00% (44/2198) in Chinese cohort, the alternation frequency of CREBBP in Chinese cohorts was lower. In TCGA cohort, the level of infiltration of tumor-related immune cells, including CD8+ T cell, CD4+ T cell, T cell regulatory (Tregs) and NK cell, were all significantly increased in mutant tumors compared with wild-type tumors (Wilcoxon test, p &amp;lt; 0.05). The mutant tumors with significantly higher inferred M1 macrophages than wild-type (p=0.0029), but not in M2 macrophages. In the Chinese cohort, the TMB level was higher in mutant group compared to wild-type group (median TMB, mut vs. wt = 82.26 vs. 7.26 Mut/Mb, p &amp;lt; 0.001). There was an elevated PD-L1 expression in CREBBP mutant tumors (29.63%, n=44) compared to wild-type tumors (15.73%, n=2154, p = 0.062). The survival analysis was performed on patients in MSKCC CRC patients treated with ICIs. The overall survival (OS) of CREBBP mutation group (n=16) were significantly longer than wild-type group (n=94) (median OS, mutation vs. wild-type = 34 vs. 13 months; HR 0.23[95% CI 0.07-0.75]; P = 0.008). Conclusion: The CREBBP gene mutation was associated with higher tumor-related immune cell infiltration and TMB level. CRC patients harboring CREBBP mutation might be a survival benefit from ICIs. Citation Format: Youen Lin, Jiewei Zheng, Tingting Chen, Wenzhuan Xie, Mengli Huang. CERBBP mutation promotes antitumor immunity and as predictive biomarkers for immune checkpoint therapy in 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 1605.