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

Tumor models created from KP subcutaneous tumors or GEMM lung tumors treated with anti–PD-(L)1 display intrinsic resistance when rechallenged in vivo.

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Tumor models created from KP subcutaneous tumors or GEMM lung tumors tre...
(A) Schematic illustrating the development of anti–PD-1– or anti–PD-L1–resistant KP tumor models. Tumors were generated either with subcutaneous implantation models using syngeneic 344SQ KP murine lung cancer cells or from autochthonous lung tumors developed in the KrasLA1-G12D/p53R172HΔg GEMM. Mice were then treated with IgG control or PD-1/PD-L1 axis–blocking antibodies until the development of resistance. At this point, tumors were excised, cultured, and expanded ex vivo, and then reimplanted into wild-type (WT) mice for rechallenge with anti–PD-(L1). (B) Three of the 344SQ IgG-treated tumors described in A (344SQPD1S) were implanted into WT mice and treated with either IgG or anti–PD-1. Tumors were measured weekly with calipers. n = 5 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 by multiple t tests (1 per time point). (C) The anti–PD-1–treated tumors described in A (344SQPD1R) were implanted and treated as in B. (D) KrasLA1-G12D/p53R172HΔg mice were imaged by micro-CT to confirm lung nodule formation. Mice were randomly distributed into IgG or anti–PD-L1 treatment arms and treated for 4 weeks. Endpoint images using micro-CT were taken (left). The percentage change in tumor area was measured for 3 independent tumors per mouse (right). (E) Cell lines were derived from the IgG-treated (KPIgG) or anti–PD-L1–treated (KPPDL1) GEMMs described in D and implanted into WT mice. Mice were rechallenged with anti–PD-L1 or IgG control antibodies and tumor response measured over time using calipers. n = 5 mice per group. **P < 0.01, ***P < 0.001 by multiple t tests (1 per time point). (F) 344SQPD1S and 344SQPD1R cells were analyzed for PD-L1 expression by Western blotting (see supplemental material for full, uncut gels). Actin was used as a loading control.