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Page 250 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

INTRODUCTION
The prostate, an exocrine gland located beneath the urinary bladder and surrounding the urethra, is
essential for male reproductive function. During embryonic development, epithelial buds from the
urogenital sinus interact with mesenchyme, driving prostate differentiation and secretory duct
[1-3]
formation . Cancer of the prostate gland, the most diagnosed cancer in men and the second-leading cause
[4-6]
of male cancer deaths in the United States, typically progresses slowly . Prostate cancer incidence and
mortality rates are closely linked to aging. Additionally, in the United States, African American men have a
[4,7]
higher incidence rate of developing aggressive prostate cancer compared to their Caucasian counterparts .
While localized disease responds well to surgery or radiation, 20% to 50% of patients experience biochemical
[7]
recurrence within a decade, leading to advanced or metastatic cancer . The prostate stroma plays a critical
role in promoting the progression of advanced prostate cancer .
[8]

In adult differentiated biology, the physical and biochemical interactions between the epithelial cells
together with cellular and non-cellular components of the stroma regulate normal prostate function and
homeostasis . The prostate stroma is composed of smooth muscle cells, tissue-resident mesenchymal cells,
[9]
extracellular matrix (ECM) proteins, nerves, blood vessels, and a spectrum of immune cells [Figure 1] [9-11] .
During development, androgen secreted by the testis is the chief regulator of prostate gland growth, and the
hormonal action is mediated through the androgen receptor (AR) . However, tissue recombination
[12]
experiments have revealed that the androgenic effects on prostate gland growth and development are not
solely dependent on epithelial AR but require paracrine signaling induced by the AR-positive prostate
mesenchyme [13,14] . Disruptions in the functional coupling between the stromal and epithelial interactions in
the adult prostate are associated with glandular dysfunction typified in aging and disease, although specific
mechanisms remain undefined. Considerable evidence suggests these biological disruptions are associated
with a transition into a repair-centric, emergency, or emergent tissue systems biology state to affect rapid
repair until the biological priority resets to functional, differentiated biology . However, an unresolved/
[15]
chronic repair state of the stroma, defined as reactive stroma, has been correlated with promoting the
evolution of pathological processes including benign prostate hyperplasia (BPH) and prostate cancer [15-18]
[Figure 1].

Currently, there is very limited information available on both tissue-resident immune cells in healthy adult
prostate and the modulations that occur in the immune landscape in a disease state like cancer. Often co-
evolving with cancer, the reactive stroma is an environment enriched with growth factors and characterized
by increased angiogenesis, an increased inflammatory response, and an extensively remodeled ECM
resulting in a desmoplastic reaction [11,19] . The reactive stroma of solid tumors, including prostate cancer, has
been shown to be immunosuppressive and associated with induced resistance to tumor-targeted
immunotherapies; however, the mechanisms remain complex [20,21] . Recent studies have shown that either
reprogramming subsets of stromal cells or immunotherapies targeting stromal antigens can disrupt the pro-
tumorigenic microenvironment niche and enhance endogenous or vaccine-induced antitumor
immunity [20-24] . In this review, we will discuss the current knowledge about stromal evolution in prostate
cancer tumorigenesis and its known regulation of the tissue-immune landscape. Understanding this will
help in developing effective therapeutic strategies that can be leveraged to co-target peri-tumoral reactive
stroma to reprogram the immune suppressive tumor microenvironment (TME) and render it permissive to
antitumor immunotherapies.

PROSTATE GLAND AT HOMEOSTASIS
An integrative network involving various cellular and acellular components regulates the structure,
function, and homeostasis of the prostate gland. The acinar epithelial cells constitute the functional