MHC-I genotype and tumor mutational burden predict response to immunotherapy
MHC-I genotype and tumor mutational burden predict response to immunotherapy
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DOI：
10.1186/s13073-020-00743-4
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发表时间：
2020-05-19
期刊：
影响因子：
12.3
通讯作者：
Kurzrock, Razelle
中科院分区：
文献类型：
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作者：
Goodman, Aaron M.;Castro, Andrea;Kurzrock, Razelle
背景 使用抑制细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 和程序性细胞死亡蛋白 1 (PD-1)（或其配体 (PD-L1)）的抗体进行免疫检查点阻断 (ICB)，可以刺激针对癌症的免疫反应，并彻底改变了肿瘤的治疗。宿主种系遗传学的影响及其与肿瘤新抗原的相互作用仍不清楚。我们试图确定肿瘤突变负荷 (TMB) 与患者 I 类主要组织相容性复合体 (MHC-I) 有效呈现突变驱动新抗原以预测 ICB 反应的能力之间的相互作用。方法 对 83 名接受 ICB 治疗的不同癌症患者进行全面的基因组分析，以确定 TMB 和人类白细胞抗原 I (HLA-I) 基因型。计算每位患者的 MHC-I 有效呈现突变驱动新抗原的能力（由患者谐波平均最佳排名 (PHBR) 评分定义（PHBR 越低表明呈现效率越高））。结果 PHBR 评分 < 0.5 与 >= 0.5 的中位无进展生存期 (PFS) 分别为 5.1 个月与 4.4 个月 (P = 0.04)。使用 10 个突变/mb 的 TMB 截止值，TMB 高/PHBR 高与 TMB 高/PHBR 低的稳定疾病 > 6 个月/部分缓解/完全缓解率、中位 PFS 和中位总生存 (OS) 分别为 43% 与 78% (P = 0.049)、5.8 个月与 26.8 个月 (P = 0.03)、以及 17.2 个月与未达到 (P = 0.23），分别。这些发现在 32 名患者的独立验证队列中得到证实。结论 MHC-I 驱动突变新抗原的不良表现可能解释了为什么某些肿瘤（即使具有高 TMB）对 ICB 没有反应。
Background Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB. Methods Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient. Results The median progression-free survival (PFS) for PHBR score < 0.5 vs. >= 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients. Conclusions Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.