Figure 2 from 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

figure

posted on 2024-10-18, 10:20 authored by 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

Stronger IFN-β responses to TLR1/2 stimulation associates with longer survival after sip-T therapy. A, HRs ± 95% CIs from a Cox proportional hazards model comparing induction of each cytokine (fold mock control) after TLR1/2 stimulation with PAM3CSK4 for PRIME cohort (left) or KCI cohort (right) vs. survival; *, P < 0.05; arrowheads indicate outlier upper bound CI (KCI cohort only). Supplementary Figure S2A depicts Cox proportional HRs for all treatments and cytokines. B, Survival of patients tested for TLR1/2 responsiveness stratified by median IFN-β induction for PRIME (left) and KCI (right) cohorts; P values are from Mantel–Cox test, HR and 95% CIs are from Mantel–Haenszel test. C, Mean z-scores normalized for each cytokine and treatment were computed for the combined cohort of patients (PRIME and KCI, n = 108), excluding patients that were censored prior to 1,000 days due to incomplete follow-up. Z-scores for patients surviving >1,000 days (n = 47) are shown and reflect enrichment/depletion relative to the broader cohort; asterisk indicates FDR adjusted (within each stimulant group) t test Q < 0.05. D, Fold mock treated MFI values for IFN-β after treatment with TLR1/2 stimulation comparing patients surviving < or > 1,000 days from PRIME (top) or KCI (bottom) subcohorts from C; P values are from unpaired t test and mean + SEM is shown. E, Cox proportional hazards model derived HRs ±95% CI and P values for indicated prognostic features and IFN-β. PSA values were not available for two patients, which were excluded from these analyses (n = 104). See Supplementary Figs. S2 and S3 for extended data. MFI, mean fluorescence intensity.

History

Related Materials

1.
DOI - Is supplement to 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

ARTICLE ABSTRACT

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. 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.

Usage metrics

Keywords

Immunology Innate immunity Immunomodulation Cancer Interception Biomarkers and intervention Immunoprevention Biomarkers Diagnostic biomarkers

Licence

CC BY