Abstract 5253: SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC

Abstract Background: Colorectal cancer has become a common gastrointestinal tumor. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have shown durable responses and have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients, and research exploring the association between gene mutation and clinical benefit is limited. SMO, a gene encodes Smoothened protein, which is an important signal converter in Sonic Hedgehog (SHH) signal pathway. Studies have shown that CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring SMO mutation, suggested that SMO may be related to immune microenvironment and tumor immunity, but the association between SMO mutation and TMB or survival in metastatic Colorectal Cancer(mCRC) is unknown. Methods: Genomic and survival data of mCRC patients administrated with ICIs were retrieved from publicly accessible data (Pancancer.Samstein2018.NGS.1661) and the association between SMO mutation overall survival (OS) were analyzed using Kaplan-Meier curves and log-rank tests. The association between SMO mutation and TMB was also analyzed in this public immunotherapy-treated cohort, Wilcoxon test was used for the comparison of TMB. In addition, Genomic, immune cell infiltration data of 149 patients with Rectum Adenocarcinoma (READ) was obtained from The Cancer Genome Atlas (TCGA). The correlation analysis between immune cell infiltration and SMO mutation status was further analyzed by CIBERSORT. Statistical significance was set at p=0.05. Results: 7.3% (8/109) patients in the clinical cohort harbored SMO mutation. Survival analysis in the public cohort demonstrated that SMO mutation resulted in significantly longer OS (10.5 vs 8 months; HR, 0; p=0.035) in mCRC patients treated with ICIs. Moreover, SMO mutation is associated with higher TMB in public cohort (p<0.0001). Furthermore, the correlation analysis between immune infiltration and SMO mutation status in mCRC which was analysed in TCGA shows that M1 macrophages, CD8 T cells, Gamma Delta T cells increased significantly (p=0.048, p=0.043, p=0.002). Conclusions: This study shows that SMO mutation may serve as a potential positive biomarker of ICIs in melanoma since it relatively correlated with higher TMB. In addition, the up regulation of M1 macrophages, CD8 T cells, as well as the Gamma Delta T cells may be another potential mechanism for the better efficacy of ICIs in patients with SMO mutation. Citation Format: Jinlin Cai, Dandan Fan, Yaoxu Chen, Mengli Huang. SMO as a predicted biomarker on immunotherapy and correlated with immune infiltrates in mCRC [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 5253.