Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti–PD-1 resistance in non–small cell lung cancer
Jessica M. Konen, … , Jianjun Zhang, Don L. Gibbons
Jessica M. Konen, … , Jianjun Zhang, Don L. Gibbons
Published September 1, 2023
Citation Information: J Clin Invest. 2023;133(17):e163128. https://doi.org/10.1172/JCI163128.
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Research Article Immunology Oncology

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

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.

Authors

Jessica M. Konen, B. Leticia Rodriguez, Haoyi Wu, Jared J. Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I. Wistuba, Jianjun Zhang, Don L. Gibbons

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Figure 6

Targeting LPAR5 on CD8+ T cells significantly increases effector functions and antitumor activity.

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Targeting LPAR5 on CD8+ T cells significantly increases effector functio...
(A) CD8+ T cells were purified from murine spleens and collected for quantitative PCR analysis of LPARs, which were then normalized to LPAR1. (B) Immunofluorescence images of LPAR2, LPAR5, and LPAR6 on murine CD8+ T cells. Arrowheads denote cells with membranous LPAR. Scale bars: 10 μm; insets zoomed 150%. (C) Images from B were quantified as a fraction of LPAR+ cells compared with total nuclei (DAPI). (D) 344SQ and 344SQPD1R1 cells were implanted into mice (n = 5 mice each). After 3 weeks, tumors were processed for flow cytometry. Each tumor was separated into 3 samples and stained with LPAR2, LPAR5, or LPAR6. Histograms depict CD8+LPAR+ cells. An IgG-stained sample is shown as a negative control. (E) Quantification of the experiment in D, which was completed twice. **P < 0.01, by t test. (F) 344SQPD1R2 cells were cocultured with naive immune cells and treated with vehicle, LPAR5 inhibitor (AS2717638), or pan-LPAR inhibitor (BrP-LPA). Immune cells were then analyzed by flow cytometry. The experiment was completed twice. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA. (G–I) 344SQ cells were implanted into mice and treated with vehicle, anti–PD-1, BrP-LPA alone or with anti–PD-1, or AS2717638 alone or with anti–PD-1. n = 5 mice per group. (G) Tumor growth was monitored with calipers. ##P < 0.01 and ####P < 0.0001, by 1-way ANOVA compared with vehicle; *P < 0.05 and **P < 0.01, by 1-way ANOVA compared with anti–PD-1. (H) Tumor weight recorded at necropsy. ###P < 0.001 and ####P < 0.0001, by 1-way ANOVA compared with vehicle; *P < 0.05 and **P < 0.01, by 1-way ANOVA compared with anti–PD-1. (I) Lung metastases recorded at necropsy. *P < 0.05, by 1-way ANOVA.