Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA.
Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA.
Cancer Immunol Immunother. 2019 Jun;68(6):897-905. doi: 10.1007/s00262-019-02318-8. Epub 2019 Mar 12.
Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.
免疫检查点抑制 (ICI) 治疗改善转移性黑色素瘤患者的预后；然而，超过 60%的接受治疗的患者对 ICI 没有反应。目前的生物标志物不能可靠地解释 ICI 耐药性。鉴于 ICI 与自身免疫之间的联系，我们研究了自身免疫的遗传易感性是否调节 ICI 的疗效。在接受一线 ICI 或联合治疗的 436 名转移性黑色素瘤患者中，我们检测了 25 个与最近全基因组关联研究中的 > 2 种自身免疫性疾病相关的 SNP，以研究它们对 ICI 疗效的调节作用。我们发现，rs17388568——一种与过敏、结肠炎和 1 型糖尿病相关的风险变异体——与抗 PD-1 反应增加相关，其显著性超过了多重测试调整（OR 0.26；95%CI 0.12-0.53；p = 0.0002）。该变异体位于已确定的免疫相关基因的位点：IL2 和 IL21。我们的研究首次提供了证据，表明自身免疫遗传易感性可能调节 ICI 的疗效，这表明对自身免疫风险基因座的系统测试可能揭示 ICI 反应的个性化生物标志物。
