Journal Article

VSSP-activated macrophages mediate senescence and tumor inhibition in a preclinical model of advanced prostate cancer

Pellegrini, Laura, Pasquini, Emiliano, Bancaro, Nicoló, Attanasio, Giuseppe, Lai, Ping, Mosole, Simone, Mesa, Circe, Troiani, Martina, Colucci, Manuel, Alvarez-Arzola, Rydell, Alimonti, Andrea

2023

Overview

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Pten pc−/− ; Trp53 pc−/− tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Pten pc−/− ; Trp53 pc−/− tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Graphical abstract 5rwXuKXp78386xwRRkt56h Video abstract

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adoptive transfer / Androgen Antagonists - pharmacology / Angiogenesis / Animals / Antibodies / Antitumor activity / Biomedical and Life Sciences / Bone marrow / Cancer therapies / Castration / Cell activation / Cell Biology / Cell Line, Tumor / Cell Proliferation / Cells / Cloning / Cytokines and Growth Factors / Experiments / Genotype & phenotype / Humans / Immunomodulation / Immunotherapy / Inflammation / Life Sciences / Macrophages / Male / Mice / Patients / Prostate - pathology / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Protein-Ligand Interactions / PTEN protein / Receptors / Senescence / Tumor Microenvironment / Tumors / VSSP