Plaugher Daniel R, Childress Avery R, Gosser Christian M, Esoe Dave-Preston, Liu Jinpeng, Brainson Christine F
bioRxiv. 2025 Jul 17:2025.07.12.663845. doi: 10.1101/2025.07.12.663845.
Lung cancer remains a significant public health burden. One of the most personalized treatments uses a patient's own tumor infiltrating lymphocytes (TILs), and TIL activity is also essential for immune checkpoint inhibitor (ICI) effectiveness. Responses to immunotherapies vary due to immune-suppressive tumor microenvironments (TMEs) and limited antigen presentation. In this study, we computationally examine cell-cell signaling and transcriptional activity using single-cell RNA sequencing of lung cancer treated by inhibiting methyltransferase EZH2. We show that EZH2 inhibition shifts the TME to immunogenic signaling patterns conducive to increased T cell response, including antigen presentation and homing. T cells also showed more stem-like phenotypes. Transcriptional activity was quieter with EZH2 inhibition but revealed better interferon response, altered myeloid and B cell differentiation, and apoptotic markers. Importantly, inferred EZH2 activity showed it could perform non-methyltransferase duties vital for T cell differentiation. These results indicate that EZH2 inhibition could improve immunotherapies for lung cancer patients.
肺癌仍然是一个重大的公共卫生负担。最具个性化的治疗方法之一是使用患者自身的肿瘤浸润淋巴细胞（TILs），并且TIL活性对于免疫检查点抑制剂（ICI）的有效性也至关重要。由于免疫抑制性肿瘤微环境（TMEs）和有限的抗原呈递，免疫疗法的反应各不相同。在本研究中，我们通过对抑制甲基转移酶EZH2治疗的肺癌进行单细胞RNA测序，对细胞间信号传导和转录活性进行了计算研究。我们发现，EZH2抑制可将TME转变为有利于增强T细胞反应的免疫原性信号模式，包括抗原呈递和归巢。T细胞也表现出更多的干细胞样表型。EZH2抑制使转录活性降低，但显示出更好的干扰素反应、改变的髓系和B细胞分化以及凋亡标志物。重要的是，推断的EZH2活性表明它可以执行对T细胞分化至关重要的非甲基转移酶功能。这些结果表明，EZH2抑制可改善肺癌患者的免疫治疗。
