Targeting a STING agonist to perivascular macrophages in prostate tumors delays resistance to androgen deprivation therapy.

Autor:	Al-Janabi H; Divsion of Clinical Medicine, The University of Sheffield, Sheffield, UK., Moyes K; Divsion of Clinical Medicine, The University of Sheffield, Sheffield, UK., Allen R; Divsion of Clinical Medicine, The University of Sheffield, Sheffield, UK., Fisher M; Divsion of Clinical Medicine, The University of Sheffield, Sheffield, UK., Crespo M; The Institute of Cancer Research, London, UK., Gurel B; The Institute of Cancer Research, London, UK., Rescigno P; The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, The Institute of Cancer Research, London, UK., de Bono J; The Institute of Cancer Research, London, UK., Nunns H; NeoGenomics Laboratories Inc Aliso Viejo, Aliso Viejo, California, USA., Bailey C; Lipexogen Biotech, Baltimore, Maryland, USA., Junker-Jensen A; NeoGenomics Laboratories Inc Aliso Viejo, Aliso Viejo, California, USA., Muthana M; Division of Clinical Medicine, The University of Sheffield, Sheffield, UK., Phillips WA; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Pearson HB; Cardiff University, Cardiff, UK., Taplin ME; Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Brown JE; Division of Clinical Medicine, The University of Sheffield, Sheffield, UK., Lewis CE; Divsion of Clinical Medicine, The University of Sheffield, Sheffield, UK Claire.lewis@sheffield.ac.uk.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Jul 25; Vol. 12 (7). Date of Electronic Publication: 2024 Jul 25.
DOI:	10.1136/jitc-2024-009368
Abstrakt:	Background: Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC. Methods: We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2'3'-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT. Results: TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs. Conclusion: Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer. Competing Interests: Competing interests: No, there are no competing interests. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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