Luke Jason J, Dadey Rebekah E, Augustin Ryan C, Newman Sarah, Singh Krishna B, Doerfler Rose, Behr Sarah, Lee Patrice, Isett Brian, Deitrick Christopher, Li Aofei, Joy Marion, Reeder Carly, Smith Katelyn, Urban Julie, Sellitto Lorenzo, Jelinek Mark, Christner Susan M, Beumer Jan H, Villaruz Liza C, Kulkarni Aditi, Davar Diwakar, Poklepovic Andrew S, Najjar Yana, Zandberg Dan P, Soloff Adam C, Bruno Tullia C, Vujanović Lazar, Skinner Heath D, Ferris Robert L, Bao Riyue
Hillman Cancer Center, UPMC, Pittsburgh, PA, USA.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Res Sq. 2023 Aug 19:rs.3.rs-3183496. doi: 10.21203/rs.3.rs-3183496/v1.
Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8 T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described. Here we identify tumor cell p38 signaling as a therapeutic target to potentiate anti-tumor immunity and overcome resistance to immune-checkpoint inhibitors (ICI). Molecular analysis of tumor tissues from patients with human papillomavirus-negative head and neck squamous carcinoma reveals a p38-centered network enriched in non-T cell-inflamed tumors. Pan-cancer single-cell RNA analysis suggests that p38 activation may be an immune-exclusion mechanism across multiple tumor types. P38 knockdown in cancer cell lines increases T cell migration, and p38 inhibition plus ICI in preclinical models shows greater efficacy compared to monotherapies. In a clinical trial of patients refractory to PD1/L1 therapy, pexmetinib, a p38 inhibitor, plus nivolumab demonstrated deep and durable clinical responses. Targeting of p38 with anti-PD1 has the potential to induce the T cell-inflamed phenotype and overcome immunotherapy resistance.
对免疫检查点抑制无反应的肿瘤患者通常具有非T细胞炎症性肿瘤微环境，其特征是缺乏与IFN-γ相关的CD8 T细胞和树突状细胞激活。了解无反应患者免疫排斥的分子机制可能有助于开发新的联合疗法。p38丝裂原活化蛋白激酶（p38 MAPK）是已知的树突状细胞和髓样细胞调节剂，然而其肿瘤内在的免疫调节作用此前尚未见报道。在此，我们确定肿瘤细胞p38信号传导是增强抗肿瘤免疫力和克服对免疫检查点抑制剂（ICI）耐药性的治疗靶点。对人乳头瘤病毒阴性头颈部鳞状细胞癌患者肿瘤组织的分子分析显示，在非T细胞炎症性肿瘤中富含以p38为中心的网络。泛癌单细胞RNA分析表明，p38激活可能是多种肿瘤类型的一种免疫排斥机制。癌细胞系中的p38基因敲低增加T细胞迁移，临床前模型中p38抑制加ICI显示出比单一疗法更高的疗效。在一项针对PD1/L1治疗难治性患者的临床试验中，p38抑制剂培美替尼加纳武单抗显示出深度且持久的临床反应。用抗PD1靶向p38有可能诱导T细胞炎症表型并克服免疫治疗耐药性。
