Epigenetic factors play important roles in tumor immunology. Histone-lysine N-methyltransferase 2 (KMT2) family genes exert histone H3 methylation, but its role in immunotherapy remains unclear. Our study is the first to investigate the correlation between KMT2 gene mutations and the clinical benefit of immune checkpoint inhibitors (ICI) treatment. We firstly collected a primary ICI-treated cohort (n = 546) and found that patients with KMT2A/C mutations yielded better prognosis in terms of progression-free survival (PFS, Hazard ratio [HR] = 0.66, P = 0.002), objective response rate (ORR, 40.9% vs 20.3%, P < 0.001), durable clinical benefit (DCB, 48.3% vs 29.8%, P = 0.001) and overall survival (OS, HR = 0.70, P = 0.033). Furthermore, we validated the predictive potential of KMT2A/C mutations in an expanded ICI-treated cohort (n = 1395). KMT2A/C-mutant patients achieved better OS compared with KMT2A/C-wildtype patients (HR = 0.68, P = 0.003); and the survival advantages appeared in the majority of cancer subtypes. Our study suggests that KMT2A/C mutations function as a novel and potential predictive biomarker for ICI treatment in multiple solid tumors and the underlying mechanism is worth investigating.

中文翻译：

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KMT2A / C突变可作为实体肿瘤免疫治疗的潜在预测生物标志物

表观遗传因素在肿瘤免疫学中起重要作用。组蛋白赖氨酸N-甲基转移酶2（KMT2）家族基因发挥组蛋白H3甲基化作用，但其在免疫治疗中的作用仍不清楚。我们的研究首次调查了KMT2基因突变与免疫检查点抑制剂（ICI）治疗的临床获益之间的相关性。我们首先收集了一个由ICI治疗的主要队列（n = 546），发现具有KMT2A / C突变的患者在无进展生存期方面有更好的预后（PFS，危险比[HR] = 0.66，P = 0.002），客观缓解率（ORR，40.9％vs 20.3％，P <0.001），持久的临床获益（DCB，48.3％vs 29.8％，P = 0.001）和总生存期（OS，HR = 0.70，P = 0.033）。此外，我们在扩大的ICI治疗组（n = 1395）中验证了KMT2A / C突变的预测潜力。与KMT2A / C野生型患者相比，KMT2A / C突变患者的OS更好（HR = 0.68，P = 0.003）；并且生存优势出现在大多数癌症亚型中。我们的研究表明，KMT2A / C突变可作为多种实体瘤中ICI治疗的新型且潜在的预测生物标志物，其潜在机制值得研究。