Läubli et al. show that the tyrosine kinase inhibitor axitinib not only blocks VEGF receptors, but also reduces the immunosuppressive environment of MC38 and LLC1 tumors by decreasing immune-inhibitory mast and myeloid cell populations. Depletion of CD4+ and CD8+ T cell populations prior to axitinib administration demonstrated that the axitinib effects are mediated via T cells. Axitinib reduced intratumoral PD1+/TIM-3+ exhausted CD8+ T cells, and synergized with checkpoint inhibitors (anti-PD-1 and/or anti-TIM-3) or a CD137 agonist.
Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF-VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.
Author Info: (1) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. heinz.laeubli@unibas.ch. Divisi
Author Info: (1) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. heinz.laeubli@unibas.ch. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. heinz.laeubli@unibas.ch. (2) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400, Biberach an der Riss, Germany. (3) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. (4) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. (5) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. (6) Laboratory of Cancer Immunology, Department of Biomedicine, University Hospital and University of Basel, Hebelstr. 20, 4031, Basel, Switzerland. alfred.zippelius@usb.ch. Division of Oncology, Department of Internal Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. alfred.zippelius@usb.ch.
