Department of Immunoregulation, Immunology and Immunotherapy Direction, Center of Molecular Immunology, Havana, Cuba.
Department of Molecular Oncology, Institute of Oncology Research (IOR), 6500, Bellinzona, Switzerland.
Cell Commun Signal. 2023 Apr 13;21(1):76. doi: 10.1186/s12964-023-01095-3.
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; Trp53 tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Pten; Trp53 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. Video abstract.
雄激素剥夺疗法（ADT）是前列腺癌（PCa）的标准疗法。尽管转移性疾病最初对 ADT 敏感，但相当一部分患者会进展为去势抵抗性前列腺癌（CRPC）。因此，需要寻找新的有效治疗 CRPC 的方法。聚焦于巨噬细胞作为抗肿瘤效应物的免疫治疗策略，直接增强其在肿瘤微环境中的细胞毒性潜力，或在体外激活后进行过继转移，已成为多种癌症类型的有前途的治疗方法。尽管有几种方法集中在激活前列腺癌中的肿瘤相关巨噬细胞（TAMs），但迄今为止，患者没有临床获益的证据。此外，巨噬细胞过继转移对前列腺癌的有效性证据不足。在这里，我们发现 VSSP 是一种骨髓系统的免疫调节剂，当给予去势 Pten 缺陷型前列腺肿瘤荷瘤小鼠时，可减少 TAMs 并抑制前列腺肿瘤生长。在携带去势抵抗性 Pten;Trp53 肿瘤的小鼠中，VSSP 给药没有效果。然而，用 VSSP 体外激活的巨噬细胞过继转移可通过减少血管生成和肿瘤细胞增殖并诱导衰老来抑制 Pten;Trp53 肿瘤生长。总之，我们的研究结果强调了利用巨噬细胞功能编程作为 CRPC 治疗有前途的策略的原理，特别强调了体外激活的促炎巨噬细胞过继转移。视频摘要。
