Abstract
Immunotherapy initially demonstrated promising results in prostate cancer (PCa), but the modest or negative results of many recent trials highlight the need to overcome the poor immunogenicity of this cancer. The design of effective therapies for PCa is challenged by the limited understanding of the interface between PCa cells and the immune system in mediating therapeutic resistance. Prompted by our recent observations that elevated WHSC1, a histone methyltransferase known to promote progression of numerous cancers, can silence antigen processing and presentation in PCa, we performed a single-cell analysis of the intratumoral immune dynamics following in vivo pharmacological inhibition of WHSC1 in mice grafted with TRAMP C2 cells. We observed an increase in cytotoxic T and NK cells accumulation and effector function, accompanied by a parallel remodeling of the myeloid compartment, as well as abundant shifts in key ligand–receptor signaling pathways highlighting changes in cell-to-cell communication driven by WHSC1 inhibition. This comprehensive profiling of both immune and molecular changes during the course of WHSC1 blockade deepens our fundamental understanding of how anti-tumor immune responses develop and can be enhanced therapeutically for PCa.
Highlights
Accepted: 10 August 2021Modulating the immune landscape of prostate cancer (PCa) to promote anti-tumor immunity has gained enthusiasm following the initial clinical success of trials testingProvenge and Prostvac VF to stimulate immune responses against prostate acid phosphatase (PAP) and prostate specific antigen (PSA), respectively
In studies designed to understand the interplay between PCa cells and the immune system, we recently demonstrated that elevated levels of the WHSC1 enzyme limit lymphocyte infiltration in PCa tumors, reduce antigen processing and presentation, as well as repress local activation of immune pathways [8]
MCTP39 treatment resulted in tumor growth suppression, with an average reduction in tumor size of 66% in the treated group compared to the control (Figure 1A)
Summary
Accepted: 10 August 2021Modulating the immune landscape of prostate cancer (PCa) to promote anti-tumor immunity has gained enthusiasm following the initial clinical success of trials testingProvenge and Prostvac VF to stimulate immune responses against prostate acid phosphatase (PAP) and prostate specific antigen (PSA), respectively. Modulating the immune landscape of prostate cancer (PCa) to promote anti-tumor immunity has gained enthusiasm following the initial clinical success of trials testing. While several studies have reported favorable clinical outcomes, especially in patients with therapy-induced immune infiltration, PCa tumors typically show only low-level immune cell infiltration in the tumor microenvironment (TME). Elevated WHSC1 expression correlates with worse prognosis in a number of cancers [1,2,3,4,5,6,7] due to its oncogenic role in promoting cell growth and metastases; the magnitude of the effect and mechanism(s) of action of WHSC1 remain poorly understood. In studies designed to understand the interplay between PCa cells and the immune system, we recently demonstrated that elevated levels of the WHSC1 enzyme limit lymphocyte infiltration in PCa tumors, reduce antigen processing and presentation, as well as repress local activation of immune pathways [8].
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