Cabozantinib Eradicates De Novo Castrate-Resistant Pten/P53 Deficient Murine Prostate Cancer Via Activation Of Neutrophil-Mediated Anti-Tumor Innate Immunity

The majority of kinase inhibitors in cancer clinical trials have been evaluated in the context of cell autonomous induction of apoptosis. However, apoptosis can result in protumorigenic immunosuppression, which limits the durability of an anti-tumor response. Recent clinical trial data shows striking clinical and radiographic responses with kinase inhibitor cabozantinib (XL-184) in metastatic solid tumors, particularly in the context of bone metastases. However, the mechanism responsible for this robust antitumor response remain unknown. Here we show that cabozantinib eradicates poorly differentiated invasive cancer that develop in the context of prostate-specific PTEN and p53 loss, respectively, within 48 hours of cabozantinib treatment. This rapid tumor clearance was temporally associated with infiltration of mature polymorphonuclear leukocytes into the tumor bed. These anti-tumor effects of cabozantinib appear to be MET-independent, since the MET inhibitor PF-04217903 did not phenocopy the effects of cabozantinib in the prostate-specific PTEN/p53 deficient mouse model in vivo. Unexpectedly, in vitro treatment of PTEN/p53 deficient cell lines derived from murine tumors showed insignificant apoptosis, but robust extracellular release of HMGB1, a neutrophil chemoattractant, and marker of immunogenic cell death. To elucidate the relevance of an immunogenic anti-tumor mechanism in vivo, we performed RNA-seq profiling and quantitative RT-PCR analysis, which showed an acute increase in anti-tumor inflammatory cytokine gene expression signature and neutrophil activation/chemotaxis markers following acute cabozantinib treatment. Critically, blockade of neutrophil chemotaxis/trafficking with dexamethasone or depletion with anti-Ly6G antibody, reversed the effects of cabozantinib towards eradication of advanced PTEN/p53 deficient tumors. Finally, cytokine array profiling of supernatant from bone marrow metastases from castrate-resistant prostate cancer patients showed increased neutrophil markers and decreased IL-6 levels within the bone microenvironment following 6 weeks of cabozantinib treatment., thus polarizing the neutrophils into” N1” effector cells. Collectively, these results shed light on a novel anti-tumor immunogenic mechanism for cabozantinib within the tumor microenvironment of PTEN/p53 deficient tumors, which unleashes a profound innate anti-tumor immune response. These findings suggest the possibility of combination therapies of cabozantinib with T-cell checkpoint blockade or vaccine-based approaches, to augment immunologic responses in advanced cancers. Citation Format: Akash Patnaik, Kenneth Swanson, Katja Helenius, Thornley Thomas, Athalia Pyzer, Vilmosne Csizmadia, Sabina Signoretti, Todd Morgan, Yugang Wang, Olivier Elemento, Lily Wang, Elena Levantini, John Clohessy, John Asara, David Smith, Jacalyn Rosenblatt, David Avigan, Steven Balk, Lewis Cantley. Cabozantinib eradicates de novo castrate-resistant PTEN/p53 deficient murine prostate cancer via activation of neutrophil-mediated anti-tumor innate immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5497. doi:10.1158/1538-7445.AM2015-5497