Androgen Deprivation Triggers a Cytokine Signaling Switch that Induces Immune Suppression and Prostate Cancer Recurrence

Keskeiset käsitteet

Androgen deprivation therapy induces a switch in tumor necrosis factor (TNF) signaling, leading to increased expression of the chemokine CCL2 that recruits immunosuppressive tumor-associated macrophages and promotes castration-resistant prostate cancer recurrence.

Tiivistelmä

The content describes experiments using genetically engineered mouse models of prostate cancer to investigate the mechanisms underlying the response to androgen deprivation therapy (ADT) via surgical castration.

Key findings:

• Castration initially causes tumor regression, but many tumors subsequently recur within 5-10 weeks.
• Blockade of tumor necrosis factor (TNF) signaling prior to castration prevents tumor regression, suggesting TNF mediates the initial anti-tumor effects of castration.
• At late time points after castration, when tumors are beginning to recur, there is an increase in TNF levels and an expansion of a basal stem cell-like population within the tumor.
• The increase in TNF at late time points induces expression of the chemokine CCL2 via NFκB signaling.
• CCL2 signaling through the CCR2 receptor recruits immunosuppressive tumor-associated macrophages (TAMs) and decreases cytotoxic T cells, promoting a tumor-permissive microenvironment and driving castration-resistant recurrence.
• Blocking CCL2 signaling prior to castration prevents tumor recurrence, phenocopying the effects of blocking TNF signaling at the same time point.

The authors propose a model in which ADT induces a switch in TNF signaling, from an initial anti-tumor effect to a pro-tumor effect mediated by CCL2-driven immunosuppression, leading to castration-resistant recurrence.

Tilastot

Tumor volume declined by 16% or more after castration, meeting the criteria for regression.
Tumors that regressed subsequently recurred, with at least two volume increases of 11% from the volume nadir.
TNF levels in tumor tissue increased at 5 weeks post-castration.
The fraction of basal/stem-like cells (Lin-/Sca-1+/CD49f+) increased from 27% in sham-operated tumors to 38% at 25 days post-castration.
CCL2 levels in tumor tissue increased at 5 weeks post-castration.

Lainaukset

"Castration induces regression and subsequent recurrence in this GEMM, resembling the onset of castration resistant prostate cancer (CRPC)."
"At late times post-castration, when the tumor is beginning to recur in a castration resistant form, TNF induces NFκB-mediated gene expression."
"CCL2 signaling through the CCR2 receptor recruits immunosuppressive tumor-associated macrophages (TAMs) and decreases cytotoxic T cells, promoting a tumor-permissive microenvironment and driving castration-resistant recurrence."

Tärkeimmät oivallukset

Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence

by Sha,K., Zhan... klo www.biorxiv.org 12-03-2023

https://www.biorxiv.org/content/10.1101/2023.12.01.569685v2

Syvällisempiä Kysymyksiä

How might the insights from this study be leveraged to develop more effective combination therapies for castration-resistant prostate cancer?

The insights from this study provide a deeper understanding of the mechanisms underlying the development of castration-resistant prostate cancer (CRPC). By identifying the role of TNF signaling in driving the switch from an anti-tumor to a pro-tumor microenvironment following androgen deprivation, researchers can explore targeted therapies that specifically inhibit TNF or downstream signaling pathways. Combination therapies that include TNF inhibitors, CCL2/CCR2 antagonists, and potentially other immune-modulating agents could be developed to disrupt the immunosuppressive TME and prevent tumor recurrence. Additionally, the findings on the role of tumor cell stemness in TNF secretion and immune suppression suggest that targeting stem cell populations within the tumor could be a promising strategy to prevent the development of CRPC.

What other signaling pathways or immune cell populations might be involved in driving the switch from an anti-tumor to a pro-tumor microenvironment following androgen deprivation?

In addition to TNF signaling and the CCL2/CCR2 axis, several other signaling pathways and immune cell populations may play a role in driving the switch to a pro-tumor microenvironment following androgen deprivation in prostate cancer. One potential pathway is the IL-6/STAT3 signaling axis, which has been implicated in promoting tumor growth, survival, and immune evasion in various cancers, including prostate cancer. Immunosuppressive cell populations such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) could also contribute to the immunosuppressive TME in CRPC. Furthermore, the activation of alternative immune checkpoints, such as PD-L1/PD-1, may play a role in immune evasion and resistance to therapy in CRPC.

Could the observed changes in tumor cell stemness and the tumor immune microenvironment be exploited to prevent or delay the development of castration resistance in prostate cancer patients?

The observed changes in tumor cell stemness and the tumor immune microenvironment present potential therapeutic targets for preventing or delaying the development of castration resistance in prostate cancer patients. Targeting the basal stem cell-like populations that drive TNF secretion and immune suppression could be a strategy to inhibit tumor recurrence and progression to CRPC. Modulating the immune microenvironment by promoting the infiltration and activation of cytolytic T cells while inhibiting immunosuppressive cell populations like TAMs and MDSCs could enhance the anti-tumor immune response and improve treatment outcomes. Additionally, strategies that combine therapies targeting tumor cell stemness with immunomodulatory agents may offer a synergistic approach to overcome castration resistance and improve patient outcomes in prostate cancer.