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Page 134 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

phosphorylation and ubiquitination of MAGE-A11, regulated by epidermal growth factor (EGF), have also
[227]
been found to enhance AR transcriptional activity .
ROLE OF IMMUNE CELLS IN ADVANCED PROSTATE CANCER
Extensive research has delved into the complicated dynamics of immune cells in advanced prostate cancer.
Immune cells serve as the body's natural defense mechanism against various intruders, including bacteria,
viruses, and cancer cells. However, in some cases, immune cells can promote tumor growth and metastasis
by creating a favorable environment for cancer cells to proliferate and spread. Based on their immune
infiltration patterns, cancers are immunologically divided into two categories: cold tumors [Figure 3] and
hot tumors. Hot tumors are characterized by high filtration of T cells and cytotoxic T lymphocytes (CTLs),
primarily due to increased tumor mutational burden, and an increase in peptides, which activate checkpoint
amino acids .
[228]

Conversely, cold tumors exhibit low mutational burden, poor antigen expression, the presence of tumor-
associated macrophages (TAM) polarized towards a pro-tumor (M2-like phenotype), and exhausted CTLs
within the tumor or their absence at the tumor margins. PCa can be viewed as a tumor with a cold immune
system. The tumor microenvironment (TME), comprising immune cells, significantly influences cancer
development and the response to immunotherapy [228,229] .

In comparison to benign nodular hyperplasia of the prostate, prostatic adenocarcinomas have been found to
have a low density of immune cells [Figure 3] . The activity of antitumor CD8+ T cells is inhibited and
[230]
slowed down by the upregulation of nitric oxide synthase and the secretion of indoleamine 2,3-dioxygenase
(IDO) by myeloid-derived suppressor cells (MDSCs). Additionally, there is a high presence of regulatory T
cells (Tregs) compared to other cancers, along with other immune-suppressive cells like neutrophils or M2
TAM, both of which are associated with poor survival outcomes. The secretion of specific substances within
the TME, such as TGF-β and CXCR2, further supports this immunosuppressive milieu. Promisingly, the
recent clinical trial (NCT03473925) suggests that inhibiting CXCR2 may be useful for enhancing
immunotherapy [231-233] .

Due to the heightened blood flow in red bone marrow, there is an increased interaction between stromal
cells and tumor cells, and stomal cells release growth factors, angiogenic factors, and bone-resorbing factors
that promote tumor growth, with bone being the preferential site of nearly 90% of PCa metastases. The
formation and development of PCa bone metastases depend on the tumor immune
microenvironment [234-236] . In an in vivo mouse model, tumor cells disseminate and produce IL-6, which
interacts with tumor-associated macrophages (TAMs) and promotes tumor cell proliferation and
angiogenesis in bone locations. Additionally, considerable amounts of TGF-β are present in bone
metastases, where they cause CD4+ helper cells to transform into Tregs, contributing to the ineffectiveness
of immunotherapies in metastatic castration-resistant prostate cancer (mCRPC) . Focusing on the release
[237]
of different types of factors at preferred metastatic locations may therefore present a potential strategy.
Additionally, an increased ratio of M2-like to M1-like TAMs was linked to lower survival in prostate cancer
patients. The ratio of M2-like to M1-like TAMs was higher in metastatic prostate cancer than in localized
[238]
prostate cancer . Pro-tumoral TAMs, sometimes referred to as M2-like TAMs, can accelerate
angiogenesis, invasion, and immunosuppression to aid in the development and metastatic growth of
tumors. Matrix metalloproteinases (MMPs), interleukin-10 (IL-10), vascular endothelial growth factor
(VEGF), and transforming growth factor-β (TGF-β) are among the substances released by M2-like
[239]
TAMs, which promote tumor cell proliferation, survival, and migration . Antiangiogenic treatments have
demonstrated significant advantages in the treatment of various cancer types, yet their efficacy in the case of