Page 58 - Read Online

Page 148 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

Prostate cancer treatment encounters substantial hurdles due to its complex interactions with the immune
system. The tumor microenvironment fosters myeloid-derived suppressor cells (MDSCs), T regulatory cells
(Tregs), and tumor-associated macrophages (TAMs), hindering effector T cell functions. Grasping these
evasion mechanisms is crucial. The TASQ trial's focus on targeting MDSCs exhibits potential in cancer
immunotherapy. Tumors strategically create an immune-tolerant microenvironment, impeding immune-
based therapies, countered by approaches like combining vaccines with agents such as imatinib and
sunitinib. The diverse roles of T-regulatory cells (Tregs) and Th17 cells suggest promising avenues for
enhancing treatment effectiveness. Striking a balance in these dynamics could drive progress in prostate
cancer immunotherapy, necessitating further research and clinical validation.

Additionally, the complexities of treating prostate cancer have led to the exploration of diverse
immunotherapy targets. Key proteins such as PSA, widely used as a serum marker, show promise by
triggering the activation of tumor-reactive CD8+ cytotoxic T cells. PSMA, highly expressed in prostate
tumors, attains significance as both a marker and a therapeutic target, securing FDA approval for advanced
metastatic prostate cancer. PAP, plentiful in prostate tissue, displays potential in immunotherapy,
particularly evident in sipuleucel-T trials. Other targets such as PSCA, dMMR, and prostein have
demonstrated positive outcomes in both preclinical and clinical settings. A comprehensive approach
involving Trp-p8, STEAP1, and NY-ESO-1 highlights the evolving landscape of prostate cancer
immunotherapy, emphasizing the ongoing importance of research and clinical validation. Overexpressed
proteins in prostate cancer, including PTHrP, hTERT, survivin, and members of the EGFR family, present
[317]
viable targets for immunotherapy . Promising interventions, such as monoclonal antibodies, dendritic cell
vaccines, and inhibitors, demonstrate potential in preclinical models. EphA2 and SSX are under
investigation for active immunotherapy, while EpCAM and RIPK2 remain potential targets with
acknowledged challenges. Continued research is essential to optimize approaches and improve patient
outcomes in prostate cancer treatment.

In-depth studies on immune dynamics in advanced prostate cancer reveal its dual role, acting as both a
defense against intruders and inadvertently supporting tumor growth. The classification of cancers into hot
or cold tumors depends on immune infiltration. Prostate cancer, identified as a cold tumor due to its low
immune density, encounters obstacles such as MDSCs and TME suppression. The significant impact of
bones on tumor development and immunotherapy underscores the necessity for precision in treatment
strategies. Effectively addressing immune-suppressive challenges, notably the prevalence of MDSCs, is
imperative for enhancing treatment outcomes.

Revolutionary immune checkpoint inhibitors (ICIs) fortify the immune system by obstructing proteins on
immune or cancer cells, facilitating the identification and eradication of cancer cells. Prostate cancer
presents unique challenges due to factors such as low mutation rates, restricted PD-L1 expression, and
intensified immunosuppression, which can complicate the efficacy of ICIs. Although specific prostate
cancer subtypes show promise, uncertainties persist, underscoring the need for ongoing research to refine
treatment approaches. The FDA approval of Sipuleucel-T for metastatic castrate-resistant prostate cancer
signifies progress, emphasizing further exploration into biomarkers, efficacy, and toxicity to improve patient
outcomes.

Advanced prostate cancer poses substantial challenges to immunotherapy. The obstacles include sparse
neoantigens hindering immune response, low antigen levels complicating recognition, and an
immunosuppressive microenvironment. Tumor heterogeneity, DNA repair issues, and dependence on the
androgen receptor further complicate existing immunotherapies. Resistance to checkpoint inhibitors,