Vasoactive Intestinal Peptide Antagonist Enhances T cell Proliferation and Synergizes with PD-1 Antibodies to Promote Anti-Melanoma T cell Immune Responses translation missing: zh.hyrax.visibility.toc_restricted.text

Pankove, Rebecca (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/h128nd71m?locale=zh
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Abstract

Antagonism of vasoactive intestinal peptide (VIP) signaling is a novel approach to reverse immune check-point inhibitory pathways. Treatment with a peptide antagonist to VIP (VIPhyb) has been shown to enhance protective immune responses to mCMV and leukemia in murine models. While treatment with VIPhyb has reduced tumor burdens in human glioblastoma, lung cancer, and breast cancer engrafted in immune-deficient mice treated with concomitant chemotherapy, a stimulatory effect of VIPhyb on anti-cancer immunity to solid tumors has not been described. We hypothesized that VIPhyb treatment would enhance T cell activation and cytotoxicity in response to melanoma, which can be highly immunogenic. We describe herein a dose-dependent enhancement of in vitro T cell proliferation in response to stimulation with anti-CD3 antibodies following the addition of VIPhyb, and reversal of the suppressive effect of exogenous VIP peptide on T cell proliferation. VIPhyb synergistically enhanced T cell proliferation in vitro when combined with anti-PD1 antibodies. 

To test the effect of blocking VIP-signaling on anti-cancer immune responses to solid tumors, mice bearing B16 melanoma tumors were treated with daily injections of VIPhyb. VIPhyb-treated mice had more effector CD8+ T cells compared with saline-treated controls, but single-agent VIPhyb treatment did not have a significant effect on the kinetics of tumor growth. Combining treatment with VIPhyb and PD-1 antibodies in mice with established melanoma, we found significantly enhanced suppression of tumor growth and improved survival compared with mice treated with either inhibitor alone or saline-treated controls. VIPhyb-and anti-PD1 antibody treatment synergistically enhanced T cell mediated immunity as assessed by increased numbers of effector CD8+ T cells. 

Notably, VIPhyb treatment did not inhibit melanoma growth, invasiveness, or change expression of immunological surface ligands in vitro. We hypothesize that treatment of mice with VIPhyb induced adaptive immunity against melanoma by down-regulating co-inhibitory pathways and stimulating T cell survival through inhibition of NF-kB signaling leading to increased numbers of cytotoxic CD8+ T cells. Thus, blocking signaling through the VIP receptor represents a new strategy to induce anti-tumor immunity in solid tumor immune-oncology. 

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