Mahadevan Navin R, Knelson Erik H, Wolff Jacquelyn O, Vajdi Amir, Saigí Maria, Campisi Marco, Hong Deli, Thai Tran C, Piel Brandon, Han Saemi, Reinhold Bruce B, Duke-Cohan Jonathan S, Poitras Michael J, Taus Luke J, Lizotte Patrick H, Portell Andrew, Quadros Victor, Santucci Alison D, Murayama Takahiko, Cañadas Israel, Kitajima Shunsuke, Akitsu Aoi, Fridrikh Maya, Watanabe Hideo, Reardon Brendan, Gokhale Prafulla C, Paweletz Cloud P, Awad Mark M, Van Allen Eliezer M, Lako Ana, Wang Xi-Tao, Chen Benjamin, Hong Fangxin, Sholl Lynette M, Tolstorukov Michael Y, Pfaff Kathleen, Jänne Pasi A, Gjini Evisa, Edwards Robin, Rodig Scott, Reinherz Ellis L, Oser Matthew G, Barbie David A
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
Cancer Discov. 2021 Aug;11(8):1952-1969. doi: 10.1158/2159-8290.CD-20-0913. Epub 2021 Mar 11.
Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC I subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection..
小细胞肺癌（SCLC）具有高度突变性，但对免疫检查点阻断（ICB）产生持久反应的情况却很罕见。SCLC还表现出细胞可塑性，这可能会影响其免疫生物学特性。在此，我们发现一个独特的SCLC亚群能够独特地上调主要组织相容性复合体I类分子（MHC I），富集具有持久ICB益处的细胞。建模证实，在神经内分泌分化丧失后，SCLC中MHC I的表观遗传得以恢复，这与干扰素基因刺激蛋白（STING）的去抑制相关。短暂抑制EZH2可使这些非神经内分泌细胞扩增，这些细胞表现出内在的先天免疫信号传导，并基本恢复了抗原呈递功能。与这些发现一致，在同基因模型中，小鼠非神经内分泌SCLC肿瘤被排斥，免疫优势效应性CD8 T细胞发生克隆性扩增。在治疗方面，抑制EZH2后再使用STING激动剂可增强小鼠体内T细胞对SCLC的识别和排斥作用。总之，这些数据将MHC I确定为SCLC免疫反应性的一种新型生物标志物，并提出了利用SCLC内在免疫原性的新型免疫治疗方法。意义：SCLC免疫原性较差，对ICB反应适度，持久活性罕见。在分析其可塑性时，我们发现了与持久ICB益处相关的非神经内分泌SCLC的内在免疫原性MHC I亚群。我们还发现，联合抑制EZH2和使用STING激动剂可揭示这种细胞状态，使细胞引发免疫排斥反应。
