Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer

Abstract

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been implicated in a variety of pathological conditions including solid cancers. In PCa, Tregs and MDSCs are attracted to TME by low-grade chronic inflammatory signals, while tissue-resident type 2 macrophages are induced by cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) produced by Th2 cells. These then drive tumor progression, therapy resistance and the generation of castration resistance, ultimately conferring a poor prognosis. The biology of MDSC and Treg is highly complex and the development, proliferation, maturation or function can each be pharmacologically mediated to counteract the immunosuppressive effects of these cells. Herein, we present a critical review of Treg, MDSC and M2 involvement in PCa progression but also investigate a newly recognized type of immune suppression induced by the chronic stimulation of the sympathetic adrenergic signaling pathway and propose targeted strategies to be used in a combinatorial modality with immunotherapy interventions such as ICB, Sipuleucel-T or antitumor vaccines for an enhanced anti-PCa tumor immune response. We conclude that a strategic sequence of therapeutic interventions in combination with additional holistic measures will be necessary to achieve maximum benefit for PCa patients.

Natural Product-Based Studies for the Management of Castration-Resistant Prostate Cancer: Computational to Clinical Studies

“…For a prevalent illness like PCa, little is known about its genesis, and only a few risk factors have been discovered ( Lin et al, 2021 ). Several factors are responsible for changes in its prevalence at the regional level due to changes in the susceptibility of different population groups to environmental risk factors, including racial/ethnic backgrounds, geographical heterogeneity, advancing age and an intact hypothalamic-pituitary-gonadal axis, family history, genetic mutations (e.g., BRCA1 and BRCA2), and diagnosis and access to good quality treatment ( Hoimes and Kelly, 2009 ; Rebbeck et al, 2013 ; Shackleton et al, 2021 ). PCa incidence and death rates differ significantly between ethnic groups, implying ethnic and genetic susceptibility ( Shackleton et al, 2021 ).…”

Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment

“…CD8+ cytotoxic T lymphocytes isolated from prostate cancer appear to have undergone clonal expansion in response to a certain antigen as they exhibit restricted T cell receptor Vβ gene usage 25 ; however, in some patients, near 90% of these prostate‐infiltrating CD8+ T cells are positive for programmed cell death protein 1 (PD‐1), 25 a cell surface immune‐suppressive checkpoint protein associated with self‐tolerance by suppressing T cell immune activity. These PD‐1 expressing cytotoxic T cells are likely incapable of mounting an effective immune response 25–28 . Cytotoxic T cell activity of killing tumor cells can also be weakened by the cancer cell production of decoy molecules against Fas and TRAIL‐induced death pathways (i.e., decoy receptor 3 [DcR3] and decoy receptor 4 [DcR4, aka TRAILR4]) 29 .…”

“…Furthermore, regulatory T (T reg ) cells and their expression of immune checkpoint cytotoxic T‐lymphocyte‐associated protein 4 (CTLA‐4) may also play pivotal roles in suppressing the antitumor immunity in prostate cancer. A study showed that upregulation of CTLA4 and its mediated immune tolerance were identified in more than half of prostate cancer patients 28 . Among prostate cancer patients with immunologic ignorance, more than 10% had a combination of PD‐1, CTLA4, and DcR3 all three mechanisms 28 .…”

“…A study showed that upregulation of CTLA4 and its mediated immune tolerance were identified in more than half of prostate cancer patients 28 . Among prostate cancer patients with immunologic ignorance, more than 10% had a combination of PD‐1, CTLA4, and DcR3 all three mechanisms 28 . These observations provide an important basis for further efforts aimed at combined immunotherapy for prostate cancer.…”

Immunophenotype Rearrangement in Response to Tumor Excision May Be Related to the Risk of Biochemical Recurrence in Prostate Cancer Patients

“…Many cancers, including PCa, are known to elicit an overproduction of a range of immunocyte suppressors, including immature myeloid cells, which recently were categorized as myeloid-derived suppressor cells (MDSCs) [14][15][16][17]. Tumor excision response of MDSC in PCa patients has also been reported [15].…”