Targeting the Immunosuppressive Microenvironment of Prostate Cancer to Enhance Therapeutic Efficacy of the Immune Checkpoint Inhibitors
Abstract
Even though there are high initial response rates of prostate cancer (PCa) patients to the androgen-deprivation therapy (ADT) and anti-androgens, the castration-resistant prostate cancer (CRPC) invariably occurs with poor prognosis and limited treatment options, which urges for more efficacious and longer-lasting novel therapies and combinations to achieve better clinical outcomes and improve survival rates for PCa patients. Cancer evades host immune system attack by inhibiting T cell activation through the interactions of the immune checkpoint proteins (ICPs), such as the programmed cell death protein 1 (PD-1) expressed by T cells and their ligands, such as PD ligand 1/2 (PD-L1/2) expressed by tumor and other cells. Immune checkpoint inhibitors (ICIs) have been developed against a variety of cancers. Unlike other cancer types with high levels of genetic mutations and infiltrating lymphocytes, PCa is relatively immunologically cold and poorly responsive to immunotherapy. So far, Phase III clinical trials of the ICIs failed to show improved overall survival in PCa patients, suggesting that identifying and targeting the determinants govern the PCa response, and resistance to the ICIs are the keys for future success in the ICI-based immunotherapy in PCa. Tie2 is a receptor tyrosine kinase (RTK) for the Angiopoietin family members, Angiopoietin-1 (Angpt1), Angpt-2, and Angpt-3/4, and is expressed by endothelial cells, cancer associated fibroblasts (CAFs), and tumor cells as well as a subset of tumor-infiltrating myeloid cells, the TIE2-expressing monocytes (TEMs). Angiopoietins (Angpts) are known to promote tumor angiogenesis and tumor progression. In a castration-resistant prostate cancer (CRPC) data set, we found that Angpt1 is amplified in 51% of CRPC patients, but only in 3% of primary and androgen-deprivation therapy (ADT)-naïve PCa patients, and that Angpt1 protein is up-regulated in advanced PCa and CRPC samples. We showed that increased Angpt1 enriches immunosuppressive TEMs and reduces CD8+T cells in PCa, whereas Angpt1 knockdown displays the opposite effects. In addition, Angpt1 induces expression of SDF-1 and IL-10 in PCa and an Angpt1 inhibitor, soluble Tie2 (sTie2), sensitizes the CRPC response to an anti-PD-1 antibody, suggesting an important novel role of Angpt1 in negatively regulating the immune response of CRPCs and the potential of Angpt1 inhibitors in sensitizing the CRPC response to the ICIs. Based on our novel results, we hypothesize that Angpt1 is a major contributor of the immunosuppressive PCa microenvironment and plays a key role in inhibiting the PCa response to the ICIs by activating Tie2 RTK to (1) promote accumulation/activation of the immunosuppressive TEMs; (2) induce SDF-1 secretion by CAFs in PCa microenvironment, which in turn promotes further recruitment of the TEMs and other myeloid-derived suppressor cells (MDSCs); and (3) induce IL-10 expression by TEMs, which in turn inhibits CD8+ T cell proliferation and activation. We further hypothesize that elevated Angpt1 leads to the reduced PCa response to the ICIs, whereas Angpt1 inhibition reverses its immunosuppressive effects and sensitizes the PCa response to the ICIs, and that combined inhibition of Angpt1 and the PD-1/PD-L1 together with or without anti-androgens such as enzalutamide constitutes a novel and more efficacious therapeutic strategy against the CRPC. Three Specific Aims are proposed. Specific Aim1 is to establish that Angpt1 enriches and activates the immunosuppressive Tie2+ monocytes (TEMs) and inhibits accumulation and activation of CD8+ T cells in PCa and that Angpt1 inhibition reverses its effects and enhances the PD-1/PD-L1-inhibitor mediated anti-PCa immunity. Aim 2 is to determine the mechanisms underlying the effects of Angpt1 on the immune cells and on the PCa response to the ICIs. More specifically, we will (1) determine the effects of Angpt1 on the Tie2+ monocytes and the mechanisms underlying the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310169
Entities
People
- Qin Yu
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army