Opposing Effects of Metoclopramide and Bromocriptine on Melanoma Response to Immune Checkpoint Blockade 2303237

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Abstract Introduction Dual immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1 have been effective in treating advanced melanoma, yet the melanoma-specific survival is only ∼52%. The human population is genetically heterogeneous, and we hypothesize that this contributes to the disparate response to ICIs. Our previous studies have demonstrated that host genetics influence ICI outcomes. Genetically heterogeneous mice with subcutaneous syngeneic melanoma tumors differentially responded to dual ICIs. Genetic linkage analysis revealed that the genomic locus containing the prolactin (PRL) gene family highly associates with ICI response. Co-therapy of PRL with ICIs significantly slowed tumor growth compared to ICIs alone. Methods To pharmacologically modulate PRL, we targeted the dopamine D2 receptor (D2R) which inhibits pituitary release of PRL. We utilized FDA-approved D2R agonist bromocriptine (BRC) and antagonist metoclopramide (MCP) to lower and raise systemic PRL, respectively. Melanoma-bearing mice were administered ICIs with or without either agent. In a separate in vitro experiment, MCP was administered to melanoma cells, T cells and macrophages. Results BRC with ICIs accelerated melanoma growth and decreased intratumoral CD8 infiltration over ICIs alone, whereas MCP with ICIs had the opposite effect. Additionally, MCP reprogrammed the tumor-microenvironment toward enhanced interferon signaling, antigen presentation and macrophage activity during immune checkpoint blockade. Moreover, MCP administration increased major histocompatibility complex I and II on melanoma cells, shifted polarization of macrophages to an anti-tumor phenotype, and enhanced T cell activation in vitro. Conclusion Taken together, these results suggest that D2R pharmacologic modulation impacts ICI therapy efficacy and anti-tumor immunity in melanoma. Our findings come with an exciting opportunity to repurpose already FDA-approved drugs as potential co-therapeutics to overcome ICI resistance in advanced melanoma patients. Funding Source 1) National Cancer Institute T32CA009531 2) National Cancer Institute R37CA220482 3) National Institutes of Health P30CA022453 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

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