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 (PRR) signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that PBMC interferon (IFN)-β responses to 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 hazard ratios compared to 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-β 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.
Cancer research communications. 2024 Sep 25 [Epub ahead of print]
Michael C Brown, Vincent M D'Anniballe, David Boczkowski, Harini Kandadi, Nadeem Sheikh, William Kornahrens, Elisabeth I Heath, Archana Thakur, Wei Chen, Lawrence Lum, Frank C Cackowski, Julie Boerner, Michael D Gunn, Andrew J Armstrong, Smita K Nair
Duke University School of Medicine, Durham, NC, United States., Duke University, Durham, United States., Duke Medical Center, Durham, NC, United States., Dendreon Pharmaceuticals, Seattle, WA, United States., Dendreon (United States), Seattle, WA, United States., Duke University, Durham, NC, United States., Karmanos Cancer Center, Detroit, MI, United States., University of Virginia Cancer Center, Charlottesville, VA, United States., Wayne State University, Detroit, MI, United States., University of Virginia Health System, Charlottesville, VA, United States.