Macrophages promote anti-androgen resistance in prostate cancer bone disease

Abstract

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing–like response of ECM–receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)–tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.

Prognostic role of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, and pan-immune-inflammation value in metastatic castration-resistant prostate cancer patients who underwent 177Lu–PSMA-617

“…177 Lu-PSMA-617 therapy is almost always preferred in mCRPC with predominant bone metastases, and the findings in our study are consistent with studies revealing that macrophages, which are transformed from monocytes, are the most important key stromal cell type in bone metastatic PC. [32] In the present study, when the values before the treatment and after the 4th cycle of 177 Lu-PSMA-617 were compared, there was no significant decrease in the number of monocytes while the other peripheral blood cells decreased. Consistent with this, while no change was found in other inflammation indices, a significant increase was observed in MLR (Table 2).…”

“…[33] In another study, it was reported that monocyte-derived and bone-resident macrophages and some cytokines released from macrophages are the main causes of treatment resistance in mCRPC, especially in patients using abiraterone or enzalutamide. [32,34] Therefore, macrophages and some cytokines secreted by macrophages may be targets for mCRPC therapy., [32,33] In patients who exhibit resistance to androgen receptor signaling inhibitors and/or 177 Lu–PSMA-617 treatment, if inflammation indices such as NLR, MLR, PLR, and SII are high, it may be prudent to consider these patients as potential candidates for novel treatment strategies targeting macrophages.…”

Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer

“…Tumor‐associated macrophages (TAMs) have been causally linked to PCa growth and progression—however, these are extremely plastic cells and can have diverse functions based on their stimuli 156–158 . M2 macrophages polarized by Th2‐derived cytokines like IL‐4/10/13, TGF‐β, or prostaglandin E2 have a wound‐healing response 159,160 . Conversely, M1‐polarized macrophages are activated by IFN‐γ and TNF‐α from Th1‐helper cells and produce proinflammatory cytokines, like IL‐1β, TNF, IL‐12, and IL‐18, and engage in direct or indirect tumor‐killing activity 161,162 .…”

Taurine Inhibits Ferroptosis Mediated by the Crosstalk between Tumor Cells and Tumor‐Associated Macrophages in Prostate Cancer

“…[1] In prostate cancer (PCa), TAMs are major immune cells in the tumor microenvironment to facilitate PCa progression via enhancing PCa cell migration and metastasis, promoting drug resistance, and so on. [2][3][4][5][6] Functionally, TAMs are primarily composed of M2-type macrophages, which can be polarized by various tumor microenvironmental factors such as chemokines, cytokines and tumor-derived extracellular vesicles (EVs). [7,8] Currently, besides their promoting effects on resistance of chemotherapy and immunotherapy, TAMs are reported to be also involved in the resistance of ferroptosis by secretion of transforming growth factor beta 1.…”

“…[ 1 ] In prostate cancer (PCa), TAMs are major immune cells in the tumor microenvironment to facilitate PCa progression via enhancing PCa cell migration and metastasis, promoting drug resistance, and so on. [ 2–6 ] Functionally, TAMs are primarily composed of M2‐type macrophages, which can be polarized by various tumor microenvironmental factors such as chemokines, cytokines and tumor‐derived extracellular vesicles (EVs). [ 7,8 ]…”