MMR system is one of many cellular DNA repair mechanisms, verifying and maintaining repeat count of microsatellites during cell division. Mutations in MMR genes lead to increased genomic instability and tumor mutational burden (TMB). MMR gene mutation is known to occur in many solid tumors, including colorectal and endometrial tumors. Pembrolizumab, a PD-1 inhibitor, has recently been approved for MMR-deficient tumors regardless of their histologic origin. A minor portion of NSCLC has been reported to have traits of MMR deficiency. However, little is known regarding its biologic and clinical implications in NSCLC. Here we examined the association between the mutational status in MMR genes and change in TMB, immune cell landscape, and clinical outcome in NSCLC. We analyzed genomic, transcriptomic, and clinical data from The Cancer Genome Atlas (TCGA) database using cBioPortal of patients with lung adenocarcinoma (ADC, 522 samples) and squamous cell carcinoma (SQCC, 504 samples). We compared the group with at least one mutation (M) in 17 MMR genes (MLH1, MLH3, MSH2, MSH3, MSH4, MSH5, MSH6, PMS1, PMS2, PCNA, EXO1, POLD1, RFC1, RFC2, RFC3, RFC4, RFC5) with the group without mutation (N). The tumor immune landscape was analyzed from RNA-seq z-scores of 812 "immune metagene" signatures (Angelova M et al., 2015) which were used to predict immune infiltration of 31 distinct immune cells for each tumor sample. Among 522 samples of ADC, 9.2% (48 samples) of MMR gene mutations were found while among 504 samples of SQCC, 9.1% (46 samples) were detected. In ADC, M group did not have significant difference in TMB compared to N group (median mutation count M:206.5 N:150.5, t-test p=0.14). There was no significant difference in activated CD4 T-cell (M:31% N:30%, chi square test p=0.81), CD8 T-cell infiltration (M:35% N:26%, chi square test p=0.16) and overall survival (median M:33 N:50 months, log-rank test p=0.27). In SQCC, M group demonstrated significantly higher TMB (median mutation count M:268 N:206.5, t-test p=0.0001) compared to N group. However, activated CD4 T-cell (M:22% N:37%, chi square test p=0.04) infiltration was significantly low. CD8 T-cell infiltration (M:26% N:28%, chi square test p=0.79) did not show any significant difference. In terms of survival, although not statistically significant, there was a trend towards worse survival in M group compared to N group (median M:35 N:65 months, log-rank test p=0.07). This is the first comprehensive report describing the immunologic and clinical implication of MMR gene mutation in NSCLC. Interestingly, similar to colorectal cancer, in SQCC there was a positive correlation between MMR gene mutation and higher TMB. However, there was no clear association with activated CD8 T-cell infiltration nor any association with favorable prognosis.

Citation Format: Young Kwang Chae, Kyunghoon Rhee, Lee Chun Park, Anderson Cho, Taeyeong Ko, Sangmin Chang, Andrew Davis, Manali Bhave, Marcello Cruz, Wadw Iams. Immunologic and clinical implications of harboring mutations in mismatch repair (MMR) genes in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4608.