MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas
复制标题
DOI：
10.1101/2022.01.10.475285
复制
发表时间：
2022-01
影响因子：
11.1
通讯作者：
Lauren E. Stopfer;Nicholas J. Rettko;Owen Leddy;J. Mesfin;E. Brown;S. Winski;Bryan D. Bryson;J. Wells;F. White
中科院分区：
文献类型：
--
作者：
Lauren E. Stopfer;Nicholas J. Rettko;Owen Leddy;J. Mesfin;E. Brown;S. Winski;Bryan D. Bryson;J. Wells;F. White
结合 NRAS/BRAF 突变黑色素瘤的多种治疗策略，即 MEK/BRAF 激酶抑制剂、免疫检查点抑制剂和靶向免疫疗法，可以克服任何个体治疗的局限性，从而提高生存获益。尽管如此，最佳组合、给药顺序和给药时间仍在研究中。在这里，我们利用定量免疫肽组学来分析肽 MHC (pMHC) 库的变化，从而测量 MEK 抑制 (MEKi) 如何改变抗肿瘤免疫。这些数据揭示了一系列肿瘤抗原，其表达水平在治疗后选择性增强，其中包括每个细胞超过 1000 个拷贝的多个表位。我们利用 pMHC 特异性 T 细胞接合剂和抗体药物偶联物靶向 4 个表位，利用 MEKi 调节抗原的可调节丰度，增强 MEK 抑制后肿瘤细胞的细胞杀伤能力。这些结果强调药物治疗是通过靶向特定上调的 pMHC 来增强免疫治疗功效的一种手段，并为识别、量化和治疗靶向其他感兴趣的表位提供了方法框架。意义 NRAS/BRAF 突变黑色素瘤中的激酶抑制剂治疗可以使肿瘤对免疫治疗敏感，部分是通过增加肽 MHC 分子的平均表面呈现。在这里，我们证明 MEK 抑制选择性地提高体外和体内选定肿瘤相关抗原的表位丰度，从而增强针对这些治疗调节表位的靶向免疫治疗功效。
Combining multiple therapeutic strategies in NRAS/BRAF mutant melanoma – namely MEK/BRAF kinase inhibitors, immune checkpoint inhibitors, and targeted immunotherapies – may offer an improved survival benefit by overcoming limitations associated with any individual therapy. Still, optimal combination, order, and timing of administration remains under investigation. Here, we measure how MEK inhibition (MEKi) alters anti-tumor immunity by utilizing quantitative immunopeptidomics to profile changes in the peptide MHC (pMHC) repertoire. These data reveal a collection of tumor antigens whose presentation levels are selectively augmented following therapy, including several epitopes present at over 1000 copies-per-cell. We leveraged the tunable abundance of MEKi-modulated antigens by targeting 4 epitopes with pMHC-specific T cell engagers and antibody drug conjugates, enhancing cell killing in tumor cells following MEK inhibition. These results highlight drug treatment as a means to enhance immunotherapy efficacy by targeting specific upregulated pMHCs and provide a methodological framework for identifying, quantifying, and therapeutically targeting additional epitopes of interest. SIGNIFICANCE Kinase inhibitor treatment in NRAS/BRAF mutant melanoma can sensitize tumors to immunotherapy, in part through an increase in average surface presentation of peptide MHC molecules. Here, we demonstrate that MEK inhibition selectively boosts epitope abundance of select tumor-associated antigens in vitro and in vivo, enhancing targeted immunotherapy efficacy against these treatment-modulated epitopes.