Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels

Significance A significant pool of HER2+ breast cancer patients are either unresponsive or become resistant to standards of care. New therapeutic approaches exploiting the tumor microenvironment, including immunotherapies, are attractive. Hypoxia shapes the tumor microenvironment toward therapy resistance and metastasis. Here, we report a role for AXL receptor tyrosine kinase in the hypoxic response by promoting HIF-1α expression. Interfering with Axl in a preclinical model of HER2+ breast cancer normalizes the blood vessels and promotes a proinflammatory microenvironment that enhances immunotherapy response to reduce the primary and metastatic tumor burdens. Clinical trials so far suggest that achieving immunotherapy responses in HER2+ cancers might be challenging, and our data might provide an important insight to circumvent a roadblock. Hypoxia is an important phenomenon in solid tumors that contributes to metastasis, tumor microenvironment (TME) deregulation, and resistance to therapies. The receptor tyrosine kinase AXL is an HIF target, but its roles during hypoxic stress leading to the TME deregulation are not well defined. We report here that the mammary gland–specific deletion of Axl in a HER2+ mouse model of breast cancer leads to a normalization of the blood vessels, a proinflammatory TME, and a reduction of lung metastases by dampening the hypoxic response in tumor cells. During hypoxia, interfering with AXL reduces HIF-1α levels altering the hypoxic response leading to a reduction of hypoxia-induced epithelial-to-mesenchymal transition (EMT), invasion, and production of key cytokines for macrophages behaviors. These observations suggest that inhibition of Axl generates a suitable setting to increase immunotherapy. Accordingly, combining pharmacological inhibition of Axl with anti–PD-1 in a preclinical model of HER2+ breast cancer reduces the primary tumor and metastatic burdens, suggesting a potential therapeutic approach to manage HER2+ patients whose tumors present high hypoxic features.

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