近日，美国宾夕法尼亚大学Andy J. Minn研究组的一项最新研究，发现了干扰素的相反功能协调应对癌症免疫检查点阻断的适应性和先天免疫反应。这一研究成果于2019年8月9日发表在国际顶尖学术期刊《细胞》上。

研究人员发现，虽然抑制肿瘤IFNG信号会降低癌细胞中干扰素刺激基因（ISG）的表达，但这又能通过增强由耗竭T细胞（TEX）产生的IFNG来增加免疫细胞中的ISG表达。在具有良好抗原性的肿瘤中，这些TEX介导了排斥反应。在具有新抗原或MHC-I缺失的肿瘤中，TEX反而利用IFNG来驱动先天免疫细胞的成熟，包括PD1和TRAIL双阳性的ILC1群体。通过去除影响PD1和TRAIL的抑制性回路，阻断肿瘤IFNG信号能够促进先天免疫杀伤。因此，癌细胞和免疫细胞中的干扰素信号彼此对立，从而建立了限制适应性和先天性免疫杀伤的调节关系。在黑素瘤和肺癌患者中，这种关系的扰动与ICB反应相关，而与肿瘤突变负担无关。

据介绍，干扰素-γ（IFNG）能增强免疫功能，但又能通过PDL1促进T细胞衰竭。目前还不清楚这些相反的效应是如何整合起来影响免疫检查点封锁(ICB)的。

附：英文原文

Title: Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

Author: Joseph L. Benci, Lexus R. Johnson, Ruth Choa, Jedd D. Wolchok, Taku Kambayashi, Andy J. Minn

Issue&Volume: Volume 178 Issue 4

Abstract: Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (T EX). In tumors with favorable antigenicity, these T EX mediate rejection. In tumors with neoantigen or MHC-I loss, T EX instead utilize IFNG to drive maturation of innate immune cells, including a PD1 +TRAIL + ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.

DOI: https://doi.org/10.1016/j.cell.2019.07.019

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30784-6