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Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15 Page 259

tumor variants resistant to surveillance are selected (immune-sculpting), and the emergence of overt tumors
in an immunocompetent host (immune-escape) [161-167] .

Role of stroma in immunomodulation of the TME
The stroma plays a pivotal role in immunomodulation, posing a significant challenge to immunotherapies
in various solid tumors like pancreatic duct adenocarcinoma (PDAC), non-small cell lung cancer, ovarian
cancer, hepatocellular carcinoma, and prostate cancer [23,168-172] . However, targeting the stroma to enhance
immunotherapy efficacy and hinder tumor progression has been largely overlooked. Understanding the
complex interplay between tumor-stroma-immune components is crucial for developing innovative
therapies to modulate the TME and improve targeted cancer treatments [21,161] .

Stromal cells significantly contribute to cancer-immuno-editing by modulating the immune system through
the secretion of various chemical messengers, such as chemokines, cytokines, and prostaglandins, as well as
the ECM. In PDAC, elevated levels of the chemokine-chemokine (C-X-C motif) ligand 10 (CXCL10),
positively correlated with high stromal content, are associated with decreased median overall survival in
patients. CXCL10 expression is linked to the presence of Tregs, which exerts immunosuppressive effects,
compromising immune surveillance against cancer [21,173,174] . Additionally, the immune regulatory chemokine
CXCL5 secreted by tumor-associated macrophages (TAMs), CAFs, EC, and cancer cells themselves plays a
crucial role in recruiting neutrophils to the TME. Neutrophils, in turn, modulate the TME, promoting
tumor growth and progression, and induce anti-inflammatory M2 macrophage polarization, impairing
immune surveillance. High expression of CXCL5 is associated with poor patient survival in various cancers,
including renal, pancreatic, liver, and cervical cancer [21,175-177] .

In solid tumors, myCAF-expressing FAP exhibits immunosuppressive properties by secreting large
amounts of stromal cell-derived factor-1 (SDF-1), hindering T-cell-tumor interactions and attracting Tregs.
+
Ablation of FAP stromal cells leads to hypoxia-induced cancer cell death mediated by interferon-γ and
[178-181]
TNF-α . Additionally, CAF-secreted TGF-β inhibits host immune surveillance by impairing dendritic
cell, M1 macrophage, NK cells, and CD8 T-cell function, while promoting Treg and Th17 cell
+
differentiation and suppressing B cell proliferation and IgA secretion [182,183] . Moreover, TGF-β restricts T-cell
[184]
infiltration, diminishing tumor response to PD-L1 blockade .
TGF-β induces ECM remodeling, while its suppression of ECM-modulating proteins like MMP-1, -8, and
-13 results in the formation of fibrotic and desmoplastic ECM matrix, which is associated with cancer
recurrence and chemoresistance [185-187] . Desmoplasia impedes T-cell recruitment into tumor nests, causing
T-cell accumulation in peri-tumoral regions and promoting immune escape. Additionally, within these
[23]
peri-tumoral regions, T cells are exposed to paracrine signals, resulting in their suppression . The
matricellular protein periostin (POSTN) is highly expressed by both tumor and stromal cells. Its elevated
expression is associated with poor prognosis in various cancers, including prostate, lung, pancreatic,
ovarian, breast, colorectal, hepatocellular, bladder, and osteosarcoma . POSTN promotes PD-1 expression
[188]
in TAMs via integrin-ILK-NF-κB signaling. PD-1-expressing TAMs were observed to induce PD-L1
[189]
expression in colorectal cancer cells, promoting immune escape . Collectively, the reactive stromal
response plays a critical role in tumor development, progression, and modulation of the immune landscape
in TME [Figure 2].

THE IMMUNE LANDSCAPE IN PROSTATE CANCER
In the past decade, the understanding of the immune landscape in cancer has evolved significantly. Studies
have utilized cell surface markers to identify various immune cell populations within the TME, including