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

ABSTRACT: 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.

SUBMITTER: Goyette MA

PROVIDER: S-EPMC8307381 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Goyette Marie-Anne MA Elkholi Islam E IE Apcher Chloé C Kuasne Hellen H Rothlin Carla V CV Muller William J WJ Richard Darren E DE Park Morag M Gratton Jean-Philippe JP Côté Jean-François JF

Proceedings of the National Academy of Sciences of the United States of America 20210701 29

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 <i>Axl</i> in a HER2<sup>+</sup> mouse model of breast cancer leads to a normalization of the blood vessels, a proinflammatory TME, and a reducti ...[more]

PMID: 34266948

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Project description:BackgroundThe efficacy of PD-(L)1 blockade depends on the composition of the tumor immune microenvironment (TIME) and is generally higher in tumors with pre-existing cytotoxic T cells (CTL) than in those with low CTL numbers. Nonetheless, a significant proportion of patients with pre-existing immunity fail to respond, indicating a therapeutic potential for combining PD-(L)1 blockade with additional immunomodulatory agents in both CTL-high and -low immune phenotypes. Here, we evaluated domatinostat (4SC-202), a class I-selective histone deacetylase (HDAC) inhibitor, for its effect on the TIME and its antitumoral efficacy using syngeneic mouse models with CTL-high or CTL-low tumors.MethodsDomatinostat was evaluated in PD-1 blockade-insensitive CTL-low (CT26) and CTL-high (C38) syngeneic models alone and in combination with different immune-inhibitory and -stimulatory approaches. Effects on the immunophenotype were assessed via flow cytometry and RNA-seq analyses. The changes in RNA-seq-based immune signatures determined in a murine setting were investigated in patient samples from the first-dose cohort of the SENSITIZE trial (NCT03278665) evaluating domatinostat combined with pembrolizumab in advanced-stage melanoma patients refractory/nonresponding to PD-1 blockade.ResultsDomatinostat increased the expression of antigen-presenting machinery (APM) genes and MHC class I and II molecules, along with CTL infiltration, in tumors of both immune phenotypes. In combination with PD-(L)1 blockade, domatinostat augmented antitumor effects substantially above the effects of single-agent therapies, displaying greater benefit in tumors with pre-existing CTLs. In this setting, the combination of domatinostat with agonistic anti-4-1BB or both PD-1 and LAG3 blockade further increased the antitumor efficacy. In CTL-low tumors, domatinostat enhanced the expression of genes known to reinforce immune responses against tumors. Specifically, domatinostat increased the expression of Ifng and genes associated with responses to pembrolizumab and nivolumab. Clinically, these findings were confirmed in patients with advanced melanoma treated with domatinostat for 14 days, who demonstrated elevated expression of APM and MHC genes, the IFNG gene, and the IFN-γ and pembrolizumab response signatures in individual tumor samples.ConclusionIn summary, these data suggest a promising potential of domatinostat in combination with immunotherapy to improve the outcome of refractory cancer patients.

Project description:BackgroundMacrophage infiltration and polarization are crucial for the pathogenesis of intracranial aneurysm (IA) rupture. Axl, a receptor tyrosine kinase, is involved in inflammation and efferocytosis in multiple organs. Upregulated soluble Axl in cerebrospinal fluid (CSF) and plasma is correlated with intracranial aneurysm rupture. This study aimed to investigate the role of Axl in IA rupture and macrophage polarization.MethodsMale C57BL/6J mice were used to induce IA. The level of Axl from control vessels and unruptured and ruptured IA samples was detected. In addition, the relationship between Axl and macrophages was confirmed. The pathway of Axl-mediated macrophage polarization was explored after IA induction in vivo and in bone marrow-derived macrophages (BMDMs) stimulated by LPS/IFN-γ in vitro. The animals were randomized into three groups and treated intraperitoneally with the vehicle, selective AXL antagonist R428, and recombinant mouse growth arrest-specific 6 (rmGas6) for 21 consecutive days. Then, we evaluated the influence of Axl on IA rupture by administrating R428 to inhibit or rmGas6 to activate the Axl receptor in vivo.ResultsCompared with that in normal vessels, Axl expression was significantly upregulated in unruptured IA samples. The ruptured IA tissue exhibited significantly higher expression of Axl than the unruptured IA tissue. Axl and F4/80 were coexpressed in IA tissue and LPS/IFN-γ-stimulated BMDMs. R428 treatment significantly reduced the rate of M1-like macrophage infiltration and IA rupture. In contrast, rmGas6 treatment promoted M1 macrophage infiltration and IA rupture. Mechanistically, R428 inhibited the phosphorylation of Axl and STAT1 and the expression of hypoxia-inducible factor-1α (HIF-1α) and decreased the levels of IL-1β, NOS2, and MMP9 in LPS/IFN-γ-stimulated BMDMs. rmGas6 promoted the phosphorylation of Axl and STAT1 and the expression of HIF-1α. In addition, STAT1 knockdown abolished Axl-mediated M1 macrophage polarization.ConclusionThe inhibition of Axl reduced macrophage polarization toward the M1 phenotype via the STAT1/HIF-1α signaling pathway and prevented IA rupture in mice. This finding suggests that pharmacological inhibition of Axl might be used to prevent the progression and rupture of IA.

Dataset Information

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

Publications

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

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