Page 84 - Read Online

Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15 Page 261

cancer model, CXCR2 knockout or antagonist administration reduced tumor growth and shifted tumor-
[205]
associated macrophages toward a pro-inflammatory M1 phenotype . Elevated neutrophil count correlates
[206]
with worse overall survival in localized prostate cancer , while elevated IL-8 levels in prostate cancer
patients with metastatic disease starting on androgen deprivation therapy (ADT) were associated with
[207]
shorter progression time to castration resistance and overall survival . Therefore, understanding the
mechanisms governing the inflammatory and immunosuppressive TME from localized disease to metastasis
is essential for developing effective immunotherapies for advanced prostate cancer.

To characterize the immune microenvironment in solid tumors like prostate cancer, numerous scientific
groups and biotechnological companies have devoted considerable efforts to developing tools for genetic,
transcriptomic, metabolic, and proteomic-based profiling of the immune landscape. These approaches
encompass serum, spatial, and single-cell-based techniques [47,208-212] . Notably, there have been significant
strides in developing immune-related gene signatures to elucidate key immune cell components within
prostate cancer, such as macrophage-based gene signatures , metabolic syndrome-based index scores ,
[213]
[210]
[217]
immune subtyping [214,215] , immune-based risk scoring , and long non-coding RNA signatures . These
[216]
advancements significantly contribute to the capacity to develop biomarkers for diagnostic and prognostic
purposes, enhancing the ability to assess the risk, progression, and sensitivity to immunotherapies in
prostate cancer.
Research efforts aimed at transforming "cold" immune microenvironments into "hot" ones in solid tumors,
including prostate cancer, are underway to enhance the efficacy of immune checkpoint inhibitors (ICIs) like
PD-1/programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)
[197]
inhibitors . However, a significant challenge in this strategy, particularly in prostate cancer, is the reactive
stromal response, which can molecularly and mechanically shield tumor cells from the antitumor immune
response. Additionally, the dysregulation of critical enzymes involved in cellular energetics within tumors,
including prostate cancer, is emerging as a hallmark feature associated with tumor evasion, though the
mechanisms are complex [218,219] . Therefore, comprehending the dynamic intercellular crosstalk between
tumor-stroma-immune cells and its subsequent modulation of the TME, which can exclude T-cell
infiltration or inhibit T-cell function, may be crucial for achieving sustainable efficacy with
immunotherapies, including ICIs, in prostate cancer [23,220] .

CURRENT STATE OF PROSTATE CANCER IMMUNOTHERAPIES
The current landscape of immune-based therapeutics for prostate cancer encompasses several approaches,
including cancer vaccines, ICIs, adoptive cell therapies, targeted antibodies, and oncolytic viral
therapy [196,221-225] . Cancer vaccines aim to stimulate the patient’s immune system, eliciting a response against
tumor-specific or tumor-associated antigens (TAA). One notable example is Sipuleucel-T, an FDA-
approved autologous vaccine that utilizes dendritic cells (DC) stimulated to target prostatic acid
phosphatase (PAP), a protein highly expressed in prostate cancer. Clinical data show evidence of improved
median survival and prolonger overall survival among men with metastatic castration-resistant prostate
cancer (mCRPC) treated with Sipuleucel-T compared to those treated with mainline treatments (anti-
hormone treatment ± chemotherapy). While Sipuleucel-T treatment has demonstrated a broad and durable
systemic immune response, clinical data suggest that the treatment provides greater benefits to patients with
a lower disease burden. This observation may be attributed to the existence of a robust immune system at
the initial stages of cancer development, in contrast to more advanced disease states. In addition, treatment
with Sipuleucel-T did not significantly affect mCRPC disease progression. This may be due to the delayed
onset of antitumor response by Sipuleucel-T, and therefore, a timeline of diagnosis of mCRPC may play an
important role in determining the maximum possible benefit from Sipuleucel-T treatment [226,227] . Additional