Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti–PD-1 resistance in non–small cell lung cancer

• Type of Material: Article
• Authors: Jessica Konen, Emory University; B. Leticia Rodriguez, University of Texas Houston; Haoyi Wu, University of Texas Houston; Jared J. Fradette, University of Texas Houston; Laura Gibson, University of Texas Houston; Lixia Diao, University of Texas Houston; Jing Wang, University of Texas Houston; Stephanie Schmidt, University of Texas Houston; Ignacio I. Wistuba, University of Texas Houston; Jianjun Zhang, University of Texas Houston; Don L. Gibbons, University of Texas Houston
• Language: English
• Date: 2023-09-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Konen et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1172%2FJCI163128
• Title of Journal or Parent Work: The Journal of Clinical Investigation
• Volume: 133
• Issue: 17
• Start Page: e163128
• Grant/Funding Information: Emory Lung Cancer SPORE CEP award; This work was supported by generous philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moon Shots Program, the Gil and Dody Weaver Foundation and Bill and Katie Weaver Charitable Trust, the Connie Rasor Endowment for Cancer Research, Rexanna’s Foundation for Fighting Lung Cancer, and MD Anderson Cancer Center Support Grant P30CA016672. Research reported in this publication was also supported in part by the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children’s Healthcare of Atlanta, and the National Institutes of Health (NIH) under award P30CA138292. Additionally, this work was supported in part by NIH grants F32CA239292 (to JMK), P50CA217691 from the Career Enhancement Program (to JMK), and in part by the Winship Cancer Institute IRG-21-137-07 from the American Cancer Society (to JMK) University of Texas Lung Cancer SPORE National Cancer Institute P50CA070907 (to DLG), and R37CA214609 (to DLG), and by Cancer Prevention and Research Institute of Texas MIRA grants RP160652 and RP200235 (to DLG).; UT Lung Cancer SPORE
• Keywords: Lung cancer; Cancer immunotherapy; Phosphodiesterases; Oncology; Immunology
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology

Abstract

Non–small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti–PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti–PD-1 and queried differential gene expression between these tumors and anti–PD-1–sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti–PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti–PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.