Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target

被引：91

作者：

Le, Xiuning ^{[1
]}

Negrao, Marcelo, V ^{[1
]}

Reuben, Alexandre ^{[1
]}

Federico, Lorenzo ^{[2
]}

Diao, Lixia ^{[3
]}

McGrail, Daniel ^{[4
]}

Nilsson, Monique ^{[1
]}

Robichaux, Jacqulyne ^{[1
]}

Munoz, Irene Guijarro ^{[1
]}

Patel, Sonia ^{[1
]}

Elamin, Yasir ^{[1
]}

Fan, You-Hong ^{[1
]}

Lee, Won-Chul ^{[1
]}

Parra, Edwin ^{[5
]}

Soto, Luisa Maren Solis ^{[5
]}

Chen, Runzhe ^{[1
]}

Li, Jun ^{[6
]}

Karpinets, Tatiana ^{[6
]}

Khairullah, Roohussaba ^{[1
]}

Kadara, Humam ^{[5
]}

Behrens, Carmen ^{[5
]}

Sepesi, Boris ^{[7
]}

Wang, Ruiping ^{[6
]}

Zhu, Mingrui ^{[8
]}

Wang, Linghua ^{[6
]}

Vaporciyan, Ara ^{[7
]}

Roth, Jack ^{[7
]}

Swisher, Stephen ^{[7
]}

Haymaker, Cara ^{[5
]}

Zhang, Jianhua ^{[6
]}

Wang, Jing ^{[2
]}

Wong, Kwok-Kin ^{[9
,10
]}

Byers, Lauren A. ^{[1
]}

Bernatchez, Chantale ^{[2
,5
]}

Zhang, Jianjun ^{[1
,6
]}

Wistuba, Ignacio I. ^{[5
]}

Gibbons, Don L. ^{[1
]}

Akbay, Esra A. ^{[8
,10
]}

Heymach, John, V ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Div Basic Sci, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Div Pathol & Lab Med, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA

[8] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA

[9] NYU Perlmutter Canc Ctr, Div Hematol & Med Oncol, New York, NY USA

[10] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

JOURNAL OF THORACIC ONCOLOGY | 2021年 / 16卷 / 04期

基金：

美国国家卫生研究院;

关键词：

EGFR-mutant lung cancer; CD73; Immune T cells; CELL LUNG-CANCER; EXPRESSION; BLOCKADE; CD73; ADENOCARCINOMA; PEMBROLIZUMAB; COMBINATION; SENSITIVITY; RESISTANCE; INHIBITORS;

D O I：

10.1016/j.jtho.2020.12.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up regulated and CD73 blockade significantly inhibited tumor growth. Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/ adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC. (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

引用

页码：583 / 600

页数：18

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