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Pharmacologic targeting of the dopamine D2 receptor impacts the efficacy of immune checkpoint blockade in melanoma

Published on Tuesday, 18 August 2026

Abstract

Background: Immune checkpoint inhibitors (ICIs) have been successful in treating advanced melanoma, yet, the 10-year melanoma-specific survival is only 52%. Our prior work using genetic linkage analysis revealed that the murine prolactin (PRL) locus associates with ICI response in C57BL/6 (B6)-syngeneic B16F0 melanoma. This was validated in F1 crosses of B6 with Collaborative Cross mice selected as potential non-responders or responders in the PRL locus and directly by coadministration of PRL with ICIs which slowed B16F0 growth compared with ICIs alone. This study uses Food and Drug Administration (FDA)-approved drugs that act on the dopamine D2 receptor (D2R), which inhibits PRL release from the pituitary, and suggests the potential of this receptor as a target to improve ICI outcomes.

Methods: We used FDA-approved D2R agonist bromocriptine (BRC) and D2R antagonist metoclopramide (MCP) to lower and raise systemic PRL, respectively in vivo. PRL-locus ICI responder and non-responder animal models were employed to assess the effect of D2R modulation with ICIs on tumor growth. Immunohistochemistry, single-cell and bulk RNA sequencing, and flow cytometry were used to explore the mechanism by which pharmacologic D2R targeting impacts antitumor immunity.

Results: BRC accelerated B16F0 growth and diminished intratumoral CD8+ T cell infiltration with ICIs in a PRL-locus ICI responder model. Conversely, MCP with ICIs slowed both B16F0 and MEL11443 growth and increased intratumoral CD8+ T cell infiltration in B6 mice, a PRL-locus ICI non-responder model. Bulk RNA sequencing revealed that MCP enhanced intratumoral immune-mediated processes based on biological sex. Single-cell RNA sequencing uncovered enhanced activity of intratumoral CD8+ T cells in a PRL-locus ICI responder compared with the B6 PRL-locus ICI non-responder model. Strikingly, MCP directly enhanced major histocompatibility complex expression on B16F0 and MEL11443 cells, increased antigen-specific CD8+ T cell activation, and modulated bone marrow-derived macrophage polarization in vitro, suggesting an additional mechanism independent of PRL in promoting antitumor immunity.

Conclusions: These findings demonstrate that pharmacologic modulation of D2R impacts the efficacy of immune checkpoint blockade in murine melanoma and raise the possibility of using FDA-approved D2R targeting therapies as cotherapeutics to overcome ICI resistance in patients with advanced melanoma.

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About this publication.

- The Di Bella Method (A Fixed Part - Bromocriptine and/or Cabergoline);

- Prolactin inhibitors in oncology - In vitro, review and in vivo publications;

- The Di Bella Method (A Fixed Part - Cyclophosphamide 50mg tablets and/or Hydroxyurea 500mg tablets, one or two per day);

- The Di Bella Method (A Fixed Part - Somatostatin, Octreotide, Sandostatin LAR, analogues and/or derivatives since 1977);

- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;

- Publication, 2018 Jul: Over-Expression of GH/GHR in Breast Cancer and Oncosuppressor Role of Somatostatin as a Physiological Inhibitor (from Di Bella's Foundation);

- Publication, 2018 Sep: The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature (from Di Bella's Foundation);

- Publication, 2019 Aug: The Entrapment of Somatostatin in a Lipid Formulation: Retarded Release and Free Radical Reactivity (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of Somatostatin and Vitamin C on the Fatty Acid Profile of Breast Cancer Cell Membranes (from Di Bella's Foundation);

- Publication, 2019 Sep: Effects of somatostatin, curcumin, and quercetin on the fatty acid profile of breast cancer cell membranes (from Di Bella's Foundation);

- Publication, 2020 Sep: Two neuroendocrine G protein-coupled receptor molecules, somatostatin and melatonin: Physiology of signal transduction and therapeutic perspectives (from Di Bella's Foundation);

The Di Bella's Method: Use of Prolactin Inhibitors Cabergoline and/or Bromocriptine, Somatostatin/Octreotide analogues and/or derivatives since 1977 associated with pseudo-Metronomic Chemotherapy Cyclophosphamide and/or Hydroxyurea - together with others chemical compounds: the dosage and administration schedule must be individualised for each patient - in several Oncological Pathologies:

- A retrospective observational clinical study of triple negative breast cancer cases treated with Di Bella Method: A preliminary data;

- The Synergism of Somatostatin, Melatonin, Vitamins Prolactin and Estrogen Inhibitors Increased Survival, Objective Response and Performance Status In 297 Cases of Breast Cancer;

- Complete objective response, stable for 5 years, with the Di Bella Method, of multiple-metastatic carcinoma of the breast;

- Evaluation of the safety and efficacy of the first-line treatment with somatostatin combined with melatonin, retinoids, vitamin D3, and low doses of cyclophosphamide in 20 cases of breast cancer: a preliminary report;

- The Di Bella Method (DBM) improved survival, objective response and performance status in a retrospective observational clinical study on 122 cases of breast cancer;

- Complete objective response to biological therapy of plurifocal breast carcinoma;

- A retrospective observational study on cases of anaplastic brain tumors treated with the Di Bella Method: A rationale and effectiveness;

- Recurrent Glioblastoma Multiforme (grade IV – WHO 2007): a case of complete objective response achieved by means of the concomitant administration of Somatostatin and Octreotide – Retinoids – Vitamin E – Vitamin D3 – Vitamin C – Melatonin – D2 R agonists (Di Bella Method – DBM) associated with Temozolomide;

- The Di Bella Method DBM improved survival objective response and performance status in a retrospective observational clinical study on 23 tumours of the head and neck;

- Chronic Lymphocytic Leukemia: Long-Lasting Remission with Combination of Cyclophosphamide, Somatostatin, Bromocriptine, Retinoids, Melatonin, and ACTH;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in advanced non-small-cell lung cancer patients with low performance status;

- Somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide in chemotherapy-pretreated patients with advanced lung adenocarcinoma and low performance status;