Targeting the dopamine D2 receptor influences response to immune checkpoint inhibitor therapy of melanoma 2787

Description Immune checkpoint inhibitors (ICIs) have been effective in treating advanced melanoma, yet the objective response rate is only ∼52%. We hypothesize that germline genetic heterogeneity contributes to disparate ICI response. This is supported by our previous work showing that genetically heterogeneous mice bearing syngeneic melanoma tumors differentially respond to ICIs. Genetic linkage analysis revealed that the genomic locus containing the prolactin (PRL) gene family highly associates with ICI response. Moreover, co-therapy of PRL with ICIs significantly slowed tumor growth and increased intratumoral CD8 infiltration over ICIs alone. To pharmacologically modulate PRL levels, we targeted the dopamine D2 receptor which inhibits pituitary release of PRL. We utilized FDA-approved dopaminergic agonist bromocriptine (BRC) and antagonist metoclopramide (MCP) to lower and raise PRL respectively. BRC with ICIs accelerated melanoma growth and decreased intratumoral CD8 infiltration over ICIs alone in female but not male mice, whereas MCP with ICIs had the opposite effect. Tumor RNA sequencing revealed principal component separation by sex and pathway enrichment in immune cell exhaustion, interferon signaling and antigen presentation in male compared to female mice administered MCP. Similarly, PRL enhanced the proliferation of male, but not female, antigen-specific CD8+ T cells in vitro. Thus, dopamine D2 receptor modulation of PRL impacts ICI efficacy in a sex-dependent manner. Funding Sources - Rumble fellowship - R37 CA220482 - U-Can-Cer Vive Foundation - Pardee Foundation - DMC Foundation - T32 CA009531 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)