Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), Los Angeles, California.
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, California.
Cancer Immunol Res. 2023 Dec 1;11(12):1642-1655. doi: 10.1158/2326-6066.CIR-23-0139.
β2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss results in acquired resistance to immune checkpoint blockade (ICB) therapies. However, there have been well-documented cases of B2M-inactivated tumors responding to ICB, justifying investigation of how an antitumor immune response can be generated to tumors without surface MHC class I. We knocked out B2M in three murine models with varying baseline MHC class I expression and sensitivity to anti-programmed death receptor (PD-1) therapy and analyzed the immune responses. MC38 and YUMMER2.1 without B2M responded to anti-PD-1 alone or with an IL2 agonist, and this was mediated by CD4+ T cells and natural killer (NK) cells. The more aggressive B16 without B2M expression only partially responded to the IL2 agonist, and this was dependent on NK cells. When analyzing nearly 300 pretreatment biopsies from patients with melanoma receiving PD-1 blockade-based therapies, we found infrequent B2M mutations or homozygous loss but more frequent LOH or copy-number gains. B2M LOH was enriched in biopsies from patients without response to therapy, and these biopsies were more frequently infiltrated by activated NK cells. We conclude that in the absence of B2M, activation of CD4+ T cells and NK cells can mediate responses to murine models of PD-1 blockade therapy. In addition, in human melanoma, the intratumoral presence of activated NK cells upon partial B2M loss likely selects against tumor escape through low surface MHC class I expression.
β2-微球蛋白（B2M）是 MHC Ⅰ类分子的关键组成部分，是将肿瘤抗原呈递给 T 细胞所必需的。它的缺失会导致对免疫检查点阻断（ICB）治疗的获得性耐药。然而，已经有充分记录的 B2M 失活肿瘤对 ICB 有反应的案例，这证明了研究如何在没有表面 MHC Ⅰ类分子的情况下产生针对肿瘤的抗肿瘤免疫反应是合理的。我们在三种具有不同基础 MHC Ⅰ类表达水平和对抗程序性死亡受体（PD-1）治疗敏感性的小鼠模型中敲除了 B2M，并分析了免疫反应。没有 B2M 的 MC38 和 YUMMER2.1 对单独使用抗 PD-1 或与 IL2 激动剂反应，这是由 CD4+T 细胞和自然杀伤（NK）细胞介导的。没有 B2M 表达的更具侵袭性的 B16 仅部分对 IL2 激动剂有反应，这依赖于 NK 细胞。当分析近 300 份接受 PD-1 阻断治疗的黑色素瘤患者的预处理活检时，我们发现 B2M 突变或纯合缺失很少见，但 LOH 或拷贝数增益更常见。B2M LOH 在对治疗无反应的患者的活检中富集，这些活检中激活的 NK 细胞浸润更为频繁。我们得出结论，在没有 B2M 的情况下，CD4+T 细胞和 NK 细胞的激活可以介导对 PD-1 阻断治疗的小鼠模型的反应。此外，在人类黑色素瘤中，部分 B2M 缺失时肿瘤内激活的 NK 细胞的存在可能通过低表面 MHC Ⅰ类表达选择对肿瘤逃逸。
