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

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.

Automated summary

Non-small cell lung cancers with KRAS and TP53 mutations show partial response to anti-PD-(L)1 treatment, but most patients do not experience durable clinical benefit. In this study, mouse lung cancer models with intrinsic resistance to anti-PD-1 were developed, and differential gene expression was analyzed to identify novel resistance mechanisms. It was found that the enzyme autotaxin (ATX) and the metabolite lysophosphatidic acid (LPA) were upregulated in resistant tumors and negatively correlated with CD8+ T cell infiltration. Inhibition of ATX or its downstream receptor LPAR5, in combination with anti-PD-1, effectively restored the anti-tumor immune response and controlled tumor growth. These findings suggest that the ATX/LPA axis is an immunosuppressive pathway that hampers the response to immune checkpoint blockade in lung cancer.