Store-operated calcium signaling modulators improve a dendritic cell-based vaccine against melanoma

Abstract

ABSTRACT Dendritic cells (DCs) are crucial for eliciting cytotoxic CD8+ T cell responses against intracellular pathogens, viruses, and cancer. DC-based vaccines can stimulate both cytotoxic and humoral immunity, as well as memory against cancer. However, efficacy has remained low, leaving room for improvement. Our previous work using conditional Stim1 knock-out mice highlighted the importance of store-operated calcium entry (SOCE) in promoting DC migration, phagosome maturation, and DC-driven CD8+ T cell responses. Yet its potential as a target to improve DC-mediated immune stimulation remains incompletely understood. We hypothesized that transient pharmacological modulation of SOCE signaling could boost DC-mediated T cell activity. Here, a targeted screen of SOCE modulators identified two compounds, thapsigargin and para-bromo-2-aminoethyl diphenylborinate, that improved T cell proliferation, IL-2, and IFNG secretion in mouse and human DC:T cell co-cultures. In a B16 melanoma model, DC vaccines boosted with either compound reduced tumor growth by 50% and doubled the median survival benefit, increasing infiltration of activated CD8+ T cells, CD4+ T, natural killer, CD80+ B cells, and M1 macrophages. Neither compound affected the surface expression of MHC-I-peptide complexes, MHC-II, CD86, nor DC migration, although thapsigargin promoted antigen retention. Bulk RNA sequencing revealed instead broad changes in pathways regulating secretion, where cytokine array analysis confirmed both compounds boosted secretion of several immunomodulatory factors. Together, this work identifies SOCE as a druggable axis that may be exploited to boost DC-mediated T cell activation and improve DC-based anticancer therapies. Summary Cruz Cobo et al. identify small molecules that reprogram dendritic cells toward an immuno-stimulating secretory phenotype, revealing endoplasmic reticulum calcium signaling as a druggable axis to boost vaccine-based and T cell-mediated cancer immunotherapies. The study links broad changes in calcium-induced secretion to improved immune activation and therapeutic potency.