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. 2018 May;67(5):815-824.
doi: 10.1007/s00262-018-2136-x. Epub 2018 Feb 27.

The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models

Affiliations

The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models

Heinz Läubli et al. Cancer Immunol Immunother. 2018 May.

Abstract

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.

Keywords: Cancer immunology; Hematopoietic stem cell; Mast cell; Tumor-associated macrophage; Tyrosine kinase inhibitor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Axitinib inhibits cancer growth not only by targeting angiogenesis, but also by modulating myeloid cells. C57BL/6 mice bearing established MC38 tumors were treated with the indicated agents. Cumulative cancer growth (a) and the corresponding animal survival (b) are depicted as pooled data from two independent experiments (n = 11–12). Tumor resident mast cell densities and TAMs within the tumor-infiltrating immune cells are depicted for the MC38 (c) and the LLC1 (d) tumor models. Data are depicted as pooled data from four independent experiments (n = 8–12) for the MC38 tumor model (c) and as pooled data from two independent experiments (n = 17–22) for the LLC1 tumor model (d). MC38 (e) or LLC1 (f) tumor-bearing animals were treated with axitinib or carrier for 7 consecutive days. Naïve (untreated) animals were used as additional controls. Upon completion of the treatment animals were euthanized and spleen cell populations (HSCs, monocytes and granulocytes) analyzed using flow cytometry. Cell numbers/spleen are depicted as pooled data from four independent experiments (n = 17–22) for the MC38 cancer model (e) and as pooled data from two independent experiments (n = 8–12) for the LLC1 cancer model (f). C57BL/6 mice bearing established MC38 tumors were treated with the indicated agents. Cumulative tumor growth (g) and the corresponding animal survival (h) are depicted as pooled data from three independent experiments (n = 17–18). **p < 0.01, ***p < 0.001 determined by Student’s t test. Data are presented as mean ± SD
Fig. 2
Fig. 2
Axitinib inhibits tumor growth by targeting mast cells. C57BL/6 mice bearing established MC38 tumors were adoptively transferred with bone marrow-derived mast cells or left untreated. Cumulative tumor growth (a) and representative, isolated tumors from the respective treatment groups are depicted. b MasTreck mice and wild-type mice lacking mast cell selective expression of the diphtheria toxin receptor were treated with diphtheria toxin to deplete mast cells. Mast cell depletion was verified by flow cytometric analysis of the peritoneum. The effect of mast cell depletion (by diphtheria toxin) on tumor growth in MasTreck mice was analyzed in the LLC1 (c, d) as well as the MC38 (e, f) tumor models. Cumulative tumor growth and the corresponding animal survival are depicted as pooled data from three independent experiments (n = 14–16, a, b). Cumulative tumor growth (c, d) and the corresponding animal survival (d, f) are depicted as pooled data from two independent experiments (n = 11–12). g, h C57BL/6 wild type (WT) or MasTreck mice, bearing established MC38 tumors, were treated with diphtheria toxin (DT) and/or the indicated agents (n = 10–12). Data are presented as mean ± SD
Fig. 3
Fig. 3
Axitinib augments anti-cancer effects via adaptive T cell responses. a, b C57BL/6 mice bearing established MC38 tumors were T cell depleted using CD4 and CD8 specific antibodies or were treated with the corresponding isotype control antibodies. Two groups were further treated with axitinib or carrier for 7 consecutive days. Cumulative tumor growth (a) and the corresponding animal survival (b) are depicted as pooled data from two independent experiments (n = 12). CD8+ T cells from control and axitinib treated animals in tumors were stained for PD-1 as well as Tim-3 and analyzed by flow cytometry. A representative staining (c) and pooled data from three independent experiments (d, n = 16) are depicted. ***p < 0.001 determined by Student’s t test. Data are presented as mean ± SD
Fig. 4
Fig. 4
Axitinib synergizes with checkpoint inhibition and co-stimulatory molecules. a C57BL/6 mice bearing established LLC1 tumors were treated with the indicated agents. Animal survival is depicted as pooled data from two independent experiments (n = 11–12). b Cancer-free animals from a were re-challenged with the same tumor cells, injected into the contralateral flank. Naïve mice (n = 6) were used as control. c C57BL/6 mice bearing established MC38 tumors were treated with the indicated agents. Animal survival is depicted as pooled data from two independent experiments (n = 12). d Cancer-free animals from c were re-challenged with the same tumor cells into the contralateral flank. Naïve mice (n = 6) were used as control. Data are presented as mean ± SD

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