RECQL5 mutations as a potential efficacious predictor of immunotherapy in melanoma patients

e21547 Background: Gene mutations in DNA damage repair (DDR) pathway were reported to affect the clinical response to immune checkpoint inhibitors (ICIs) by driving mutagenicity. Previous studies showed that RECQL5 is involved in RAD51-mediated strand invasion for homologous recombination DNA damage repair (HR-DDR). RECQL5 encoding RecQ protein-like 5 (RECQL5) is a member of RecQ helicase family and was discovered to play a tumor-suppressive or oncogenic role in various cancers. However, the association between RECQL5 mutation and ICI efficacy has not been revealed. Methods: Data of nine publicly independent cohorts of NSCLC, melanoma, and pan-cancer were retrieved (Rizvi, MSKCC, OAK/POPLAR, Van Allen, Hugo, Synder, Miao and Samstein cohorts) to investigate the correlation between RECQL5 mutations and clinical events including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Wilcoxon test was used for comparing tumor mutational burden (TMB) between RECQL5-mutated patients and their wild-type counterparts. In addition, the correlation between infiltration of immune cells and RECQL5 mutation status was also analyzed by QUANTISEO using data of SKCM cohort (n=466) from TCGA database. Statistical significance was set at P = 0.05. Results: RECQL5 mutations were most commonly seen in melanoma patients and the detection rate was 4%-8% in melanoma patients from cohort Van Allen, Hugo, Synder, and Miao. RECQL5 mutation was not detected in other cancers except for one lung cancer case. In the three melanoma cohorts (Van Allen, Synder, Miao) with OS data available, the OS of the RECQL5-mutated patients was 2 to 3 times longer than that of the RECQL5-wt patients. In Synder cohort, the difference in OS between these two subsets was statistically significant (53.9 months vs 25.0 months, P = 0.045). In addition, the occurrence of RECQL5 mutations was correlated with higher CBR both in Miao ( P = 0.017) and Synder cohorts ( P = 0.011). No difference was observed in the PFS or ORR between these two subsets. Notably, RECQL5 mutations were associated with higher TMB levels both in Miao (32.6 mut/Mb vs 7.9 mut/Mb, P = 0.016) and Synder cohorts (1124 mut/Mb vs 358 mut/Mb, P = 0.033). Moreover, RECQL5 mutations were found to be correlated with increased infiltration of CD4+ T cells (no-regulatory) ( P = 0.037), B cells ( P = 0.13) and decreased infiltration of regulatory CD4+ T cells ( P = 0.02) in RECQL5-mutated tumors over RECQL5-wt tumors. Conclusions: RECQL5 mutations can serve as a potential predictor for a durable response to ICIs in melanoma. Moreover, the occurrence of RECQL5 mutations was correlated with higher TMB level as well as infiltration of immune cells, indicating the underlying mechanism of its predictive effect.