美国加州大学洛杉矶分校（UCLA）琼森综合癌症中心Antoni Ribas和Catherine S. Grasso研究组合作取得一项新突破。他们的最新研究提出保守的干扰素-γ（IFN-γ）信号驱动免疫检查点封锁治疗黑色素瘤的临床反应。这一研究成果于2020年9月10日发表在《癌细胞》杂志上。

他们分析了101例单独用nivolumab（抗PD-1）或与ipilimumab（抗CTLA-4）联合治疗的晚期黑色素瘤患者的基线和治疗中肿瘤活检的转录组。他们发现，T细胞浸润和IFN-γ信号特征与临床上治疗的反应高度一致，而在相应的活检样品中细胞周期和WNT信号传导途径则相应减少。

他们对58种人类细胞系中的相互作用进行建模，发现除非细胞IFN-γ受体改变，否则IFN-γ的体外暴露会导致保守的转录组反应。黑色素瘤细胞中这种保守的IFN-γ转录组反应可放大抗肿瘤免疫反应。因此，抗肿瘤T细胞反应的强度和相应的下游IFN-γ信号传导是临床反应或对免疫检查点封锁疗法耐药的主要驱动力。

附：英文原文

Title: Conserved Interferon-γ Signaling Drives Clinical Response to Immune Checkpoint Blockade Therapy in Melanoma

Author: Catherine S. Grasso, Jennifer Tsoi, Mykola Onyshchenko, Gabriel Abril-Rodriguez, Petra Ross-Macdonald, Megan Wind-Rotolo, Ameya Champhekar, Egmidio Medina, Davis Y. Torrejon, Daniel Sanghoon Shin, Phuong Tran, Yeon Joo Kim, Cristina Puig-Saus, Katie Campbell, Agustin Vega-Crespo, Michael Quist, Christophe Martignier, Jason J. Luke, Jedd D. Wolchok, Douglas B. Johnson, Bartosz Chmielowski, F. Stephen Hodi, Shailender Bhatia, William Sharfman, Walter J. Urba, Craig L. Slingluff, Adi Diab, John B.A.G. Haanen, Salvador Martin Algarra, Drew M. Pardoll, Valsamo Anagnostou, Suzanne L. Topalian, Victor E. Velculescu, Daniel E. Speiser, Anusha Kalbasi, Antoni Ribas

Issue&Volume: 2020-09-10

Abstract: We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patientswith advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab(anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signalingsignatures correspond most highly with clinical response to therapy, with a reciprocaldecrease in cell-cycle and WNT signaling pathways in responding biopsies. We modelthe interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptoralterations. This conserved IFN-γ transcriptome response in melanoma cells servesto amplify the antitumor immune response. Therefore, the magnitude of the antitumorT cell response and the corresponding downstream IFN-γ signaling are the main driversof clinical response or resistance to immune checkpoint blockade therapy.

DOI: 10.1016/j.ccell.2020.08.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30416-5