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

被引：403

作者：

Benci, Joseph L. ^{[1
,7
,8
,15
]}

Johnson, Lexus R. ^{[1
,8
]}

Choa, Ruth ^{[4
]}

Xu, Yuanming ^{[1
,8
]}

Qiu, Jingya ^{[1
,8
]}

Zhou, Zilu ^{[9
]}

Xu, Bihui ^{[1
,8
]}

Ye, Darwin ^{[1
,8
]}

Nathanson, Katherine L. ^{[2
,6
]}

June, Carl H. ^{[4
,6
,7
,8
]}

Wherry, E. John ^{[3
,5
,6
,7
]}

Zhang, Nancy R. ^{[9
]}

Ishwaran, Hemant ^{[10
]}

Hellmann, Matthew D. ^{[11
,12
,14
]}

Wolchok, Jedd D. ^{[11
,12
,13
,14
]}

Kambayashi, Taku ^{[4
,6
]}

Minn, Andy J. ^{[1
,6
,7
,8
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA

[7] Univ Penn, Perelman Sch Med, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[8] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[9] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA

[10] Univ Miami, Dept Epidemiol & Publ Hlth, Div Biostat, Miami, FL 33136 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[12] Mem Sloan Kettering Canc Ctr, Parker Inst Canc Immunotherapy, New York, NY 10065 USA

[13] Mem Sloan Kettering Canc Ctr, Ludwig Collaborat Lab, New York, NY 10065 USA

[14] Weill Cornell Med Coll, Dept Med, New York, NY 10065 USA

[15] Bristol Myers Squibb, Princeton, NJ 08540 USA

来源：

CELL | 2019年 / 178卷 / 04期

关键词：

NATURAL-KILLER-CELLS; I INTERFERON; PD-1; BLOCKADE; NK CELLS; CLINICAL-RESPONSE; LYMPHOID-CELLS; TUMOR-CELLS; RESISTANCE; MELANOMA; THERAPY;

D O I：

10.1016/j.cell.2019.07.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：933 / +

页数：30

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