Reduced T-cell Numbers and Elevated Levels of Immunomodulatory Cytokines in Metastatic Prostate Cancer Patients De Novo Resistant to Abiraterone and/or Enzalutamide Therapy

Abstract

Currently, there are two Food and Drug Administration (FDA)-approved drugs for androgen deprivation therapy (ADT) of metastatic castration-resistant prostate cancer (mCRPC) patients: abiraterone and enzalutamide. However, our understanding of the effect of these therapies on the immune system in mCRPC patients remains limited. Here, we examined how abiraterone and enzalutamide treatment affects levels of soluble immune mediators in plasma and in circulating immune cells of 44 mCRPC patients. We found that the baseline levels of cytokines fibroblast growth factor (FGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 10 (IL-10), and IL-6 were significantly lower in ADT-sensitive compared to de novo resistant patients. In addition, resistant patients showed significantly lower T cell frequencies. When comparing the levels of cytokines over the course of treatment, we observed that the levels of proinflammatory mediators, such as interferon-γ (IFN-γ), IL-5, macrophage inflammatory protein 1 alpha (MIP-1α), and tumor necrosis factor alpha (TNFα), were significantly increased in the ADT-sensitive patients. At the same time, the abiraterone/enzalutamide therapy did not reduce the percentage of tolerogenic myeloid cell populations, such as polymorphonuclear myeloid-derived suppressor cells, which retained unaltered expression of programmed death-ligand 1 (PD-L1) and B7-H3. Overall, our results suggest that certain immune markers, such as IL-6 and the frequency of effector T cells, could be predictive of therapeutic response to ADT therapies in mCRPC patients.

Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment

“…For example, talimogene laherparepvec (T-VEC), an oncolytic virus FDA approved for the treatment of advanced melanoma, has been engineered to selectively replicate within tumors and to promote the priming of T cell responses and produce granulocyte–macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses [ 308 ]. The role of the tumor secretome in general, and of CSCs in particular, is emerging as an indicator of the response to treatment as shown by the two FDA-approved drugs for androgen deprivation therapy for metastatic prostate cancer, abiraterone and enzalutamide, whose resistance seems to be related to a potentially immunosuppressive tumor microenvironment and whose treatment efficacy can be predicted using IL-6 levels [ 309 ].…”

Current Status and Future Perspectives of Checkpoint Inhibitor Immunotherapy for Prostate Cancer: A Comprehensive Review

“…The compromised immune system of patients with PCa is characterized by a reduction in NK cell activity and renewal and inhibited expression of CD3 in NK and T cells, which may ultimately result in the reduction of T cell receptors and NK cell-activating receptors [50][51][52]. Moreover, patients with mCRPC also have a reduced number of total T cells [53] and an increased number of myeloid suppressor cells and regulatory T cells in the tumor microenvironment and circulation [54][55][56]. Another potential explanation for the resistance and tolerance to immunotherapy in PCa is the slow disease progression [57,58].…”

Interleukin-10 Induces Expression of Neuroendocrine Markers and PDL1 in Prostate Cancer Cells

“…Another cytokine that signals through STAT3 is interleukin-10 (IL10). In fact, both IL10 and IL6 have been reported to be excessively expressed in metastatic androgen-independent PCa cells [ 13 ] and serum levels of IL10 and IL6 are elevated in patients resistant to ENZ treatment compared to sensitive patients [ 14 ]. These observations suggest that both cytokines may contribute to the development of more aggressive tumours with NE phenotype [ 15 , 16 ].…”