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Regulation of immune checkpoint inhibitor efficacy by dopamine D2 receptor signaling

Award Number: F30CA310029
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Regulation of immune checkpoint inhibitor efficacy by dopamine D2 receptor signaling - Abstract Melanoma is the most common cause of skin-cancer related death in the United States. The introduction of immune checkpoint inhibitors (ICIs) has improved survival outcomes from 6-9 months to 6-7 years, on average. However, most patients fail to respond, and many acquire treatment resistance. Our study aims to identify immune-related mechanisms of resistance to improve patient outcomes. We previously showed that host genetic background influences anti-tumor immunity and ICI outcomes in genetically heterogeneous mouse models. Host genetic linkage analysis demonstrated a strong association between prolactin and response to ICIs. Additionally, augmentation of prolactin with ICIs decreased tumor growth rate and increased intratumoral CD8 T cell infiltration relative to ICI monotherapy. This F30 proposal seeks to define the mechanisms by which pharmacologic modulation of dopamine D2 receptor (D2R)-mediated release of prolactin modulates immune activity during ICI therapy. We found that D2R blockade improved ICI response and elevated intratumoral CD8 infiltration over ICIs alone as well as enhancing tumor cell immunogenicity. In Aim 1, we will use melanoma mouse models and D2R targeting to evaluate the biological effect when combined with ICI. We will test whether D2R influences adaptive immune cell priming and/or T cell exhaustion. We will additionally determine how D2R impacts the immunogenic capacity of tumor cells. In Aim 2, we will establish the immune-mediated mechanisms of ICI response with D2R modulation. We will investigate how ICIs and D2R work together to impact the activity of T cells and myeloid cells (including antigen presenting cells) in vivo and in vitro. Together the studies described here will identify the role(s) of D2R modulation during ICI therapy, exposing actionable therapeutic targets to lay the groundwork for future translational efforts using prolactin-modulating therapy to improve ICI response in patients with metastatic melanoma. The training plan outlined in this proposal will be performed between Wayne State University School of Medicine Cancer Biology Graduate Program and Karmanos Cancer Institute, which provides a unique opportunity to leverage the advantages and expertise in both institutions to optimize research and clinical training. Executing this training plan under such a vibrant multi-institutional environment, with the guidance of dedicated sponsors, collaborators, and mentors with expertise in immunology, genetics, cancer biology, and dermatology, will provide an unmatched experience to launch a successful career as a physician-scientist.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $51,837 )
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Research Manpower	000	1	7/31/2026	NEW	$51,837
2026	2026	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Research Manpower	001	1	7/31/2026	NEW	$0
														Subtotal = $51,837

Grand Total All Awards = $51,837

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Regulation of immune checkpoint inhibitor efficacy by dopamine D2 receptor signaling

Award Number: F30CA310029

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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