Peripheral Blood IFN Responses to Toll-Like Receptor 1/2 Signaling Associate with Longer Survival in Men with Metastatic Prostate Cancer Treated with Sipuleucel-T.

Autor:	Brown MC; Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina., D'Anniballe VM; Department of Medicine, Duke University School of Medicine, Durham, North Carolina., Boczkowski D; Department of Surgery, Duke University School of Medicine, Durham, North Carolina., Kandadi H; Dendreon Pharmaceuticals, LLC, Seattle, Washington., Sheikh N; Dendreon Pharmaceuticals, LLC, Seattle, Washington., Kornahrens W Jr; Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina., Heath EI; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan., Thakur A; Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, Virginia., Chen W; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan., Lum L; Division of Hematology and Oncology, University of Virginia School of Medicine, Charlottesville, Virginia., Cackowski FC; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan., Boerner J; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan., Gunn MD; Department of Medicine, Duke University School of Medicine, Durham, North Carolina., Armstrong AJ; Department of Medicine, Duke University School of Medicine, Durham, North Carolina.; Department of Surgery, Duke University School of Medicine, Durham, North Carolina.; Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, North Carolina., Nair SK; Department of Neurosurgery, Duke University School of Medicine, Durham, North Carolina.; Department of Surgery, Duke University School of Medicine, Durham, North Carolina.; Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Oct 01; Vol. 4 (10), pp. 2724-2733.
DOI:	10.1158/2767-9764.CRC-24-0439
Abstrakt:	Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration-resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that peripheral blood mononuclear cell IFN-β responses to Toll-like receptor 1/2 (TLR1/2), a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n = 106, HR = 0.12; P = 0.019; validation cohort: n = 28, HR < 0.01; P = 0.047). Higher IFN-β induction after TLR1/2 stimulation was associated with lower HRs than biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2-dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-β; P = 0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen-specific T cells. IFN-β responses to TLR1/2 signaling correlated with increased numbers of IFN-γ producing T cells after broad, tumor antigen-independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T-cell functionality in men with mCRPC. Significance: The identification of factors that determine successful cancer immunotherapy, particularly in refractory tumor types like mCRPC, is urgently needed: both to identify patients that may benefit from such therapies and to uncover routes to sensitize patients with cancer to immunotherapy. Our work links functional peripheral immune responses with race and survival after cellular immunotherapy in men with mCRPC. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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