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Page 657 Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48

INTRODUCTION
Prostate Cancer has the second highest cancer incidence worldwide and is the 5th leading cause of cancer
[1]
death in men . The cornerstone treatment of locally-advanced and metastatic prostate cancer centres upon
androgen deprivation therapy. Patients who experience disease progression while having castrate levels of
testosterone are considered castration-resistant. In the advanced prostate cancer setting, additional
treatment modalities include novel hormonal agents (NHAs), chemotherapy, radioligand therapy,
poly(ADP)-ribose polymerase (PARP) inhibitors, and immunotherapy. Successive waves of clinical trials in
the past decade have brought these treatment modalities forth from the castration-resistant setting into the
hormone-sensitive setting, showing improved survival with early introduction of chemotherapy, NHAs, or
[2]
combinations of these . Despite these advances in prostate cancer treatment, the 5-year survival for
metastatic prostate cancer patients in 2022 remains low at 32.3% .
[3]

Immunotherapy, in the form of sipuleucel-T, received FDA approval in 2010 for the treatment of patients
with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In
patients with deficient mismatch repair or microsatellite-high (dMMR/MSI-H) tumours, pembrolizumab
[4,5]
and dostarlimab are FDA-approved options . However, the prevalence of dMMR/MSI-H in prostate
cancer is dismal at 1%, with MSH2 being the most frequently implicated (other MMR genes being MSH6,
MLH1, PMS2) . Owing to an immunologically “cold” microenvironment in unselected acinar prostate
[6]
adenocarcinoma, to date, no other immunotherapeutic agents have shown to be beneficial in the current
treatment of advanced prostate cancer. In this review, we look at the current treatment paradigm, the role of
immunotherapy, and existing and up-and-coming methods to overcome immune therapy resistance in
prostate cancer.

IMMUNE REGULATION IN THE TUMOUR MICROENVIRONMENT (TME) OF PROSTATE
CANCER
Immuno-oncology has changed the treatment paradigm of multiple tumour types, including melanoma,
renal cell carcinoma, and lung carcinoma. The cancer-immunity cycle is depicted in Figure 1, explaining
how the innate immune system fends off cancer cells and the various points at which therapeutic targets act.
Despite successes in these typically immunogenic tumours, prostate cancer has traditionally been
considered to have an immunologically “cold” tumour microenvironment (TME) characterized by T cell
exclusion, low neoantigen load, and a highly immunosuppressive microenvironment comprising a high
[7,8]
proportion of myeloid-derived suppressor cells (MDSCs) . Factors that suggest a maladaptive immune
response against tumour cells include lack of tumour-infiltrating lymphocytes (TILs), presence of
M2-polarized tumour-associated macrophages (TAMs) and MDSCs, with evidence that increment in such
cell populations within the TME is correlated with tumour progression . MDSCs are immune cells that are
[9]
activated in cancers and display potent immunosuppressive effects leading to prostate cancer resistance to
anti-hormonal therapy . Furthermore, CRPCs frequently exhibit PTEN loss, which is associated with
[10]
[11]
increased MDSC infiltration and may interact with the interferon-1 pathway required for innate immune
activation . Other immune-suppressive factors within the TME, such as soluble tumour necrosis factor
[12]
(sTNF), interleukin-1 beta (IL-1β), TGF-β, and IL-10, promote chronic inflammation and increase myeloid
cell differentiation into MDSCs [13,14] .

Reduced immune stimulatory factors can also contribute to the immunologically cold TME in prostate
cancer. CRPC patients have decreased peripheral natural killer (NK) cell pools, and this may be due to
increased NK cell group 2 member D (NKG2D) serum receptor levels from the tumour . This
[15]
phenomenon is more pronounced with metastatic disease . NK cells are lymphocytes that have roles in
[9]
innate and adaptive immunity, whereas NKG2D is an activating cell surface receptor expressed on NK cells,