TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstr. 12, 55131 Mainz, Germany.
TRON gGmbH - Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstr. 12, 55131 Mainz, Germany; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany.
Cancer Cell. 2024 Apr 8;42(4):568-582.e11. doi: 10.1016/j.ccell.2024.02.013. Epub 2024 Mar 14.
Major histocompatibility complex (MHC) class I antigen presentation deficiency is a common cancer immune escape mechanism, but the mechanistic implications and potential strategies to address this challenge remain poorly understood. Studying β2-microglobulin (B2M) deficient mouse tumor models, we find that MHC class I loss leads to a substantial immune desertification of the tumor microenvironment (TME) and broad resistance to immune-, chemo-, and radiotherapy. We show that treatment with long-lasting mRNA-encoded interleukin-2 (IL-2) restores an immune cell infiltrated, IFNγ-promoted, highly proinflammatory TME signature, and when combined with a tumor-targeting monoclonal antibody (mAB), can overcome therapeutic resistance. Unexpectedly, the effectiveness of this treatment is driven by IFNγ-releasing CD8 T cells that recognize neoantigens cross-presented by TME-resident activated macrophages. These macrophages acquire augmented antigen presentation proficiency and other M1-phenotype-associated features under IL-2 treatment. Our findings highlight the importance of restoring neoantigen-specific immune responses in the treatment of cancers with MHC class I deficiencies.
主要组织相容性复合体 (MHC) Ⅰ类抗原呈递缺陷是一种常见的癌症免疫逃逸机制，但对其机制影响和潜在策略的理解仍很有限。通过研究β2-微球蛋白 (B2M) 缺陷型小鼠肿瘤模型，我们发现 MHC Ⅰ类缺失导致肿瘤微环境 (TME) 发生实质性的免疫荒漠化，并广泛抵抗免疫、化疗和放疗。我们表明，用长效 mRNA 编码的白细胞介素-2 (IL-2) 治疗可恢复免疫细胞浸润、IFNγ 促进的、高度促炎的 TME 特征，并且与肿瘤靶向单克隆抗体 (mAB) 联合使用时，可以克服治疗抵抗。出乎意料的是，这种治疗的有效性是由识别 TME 中激活的巨噬细胞交叉呈递的新抗原的 IFNγ 释放的 CD8 T 细胞驱动的。这些巨噬细胞在 IL-2 治疗下获得增强的抗原呈递能力和其他 M1 表型相关特征。我们的研究结果强调了在治疗 MHC Ⅰ类缺陷癌症中恢复新抗原特异性免疫反应的重要性。
