The Tumor Immune Contexture of Prostate Cancer

Abstract

One in seven men in North America is expected to be diagnosed with prostate cancer (PCa) during their lifetime ( 1 , 2 ). While a wide range of treatment options including surgery, radiation, androgen deprivation and chemotherapy have been in practice for the last few decades, there are limited treatment options for metastatic and treatment resistant disease. Immunotherapy targeting T-cell associated immune checkpoints such as CTLA-4, PD-L1, and PD-1 have not yet proven to be efficacious in PCa. Tumor mutational burden, mutations in DNA damage repair genes, immune cell composition and density in combination with their spatial organization, and expression of immune checkpoint proteins are some of the factors influencing the success of immune checkpoint inhibitor therapies. The paucity of these features in PCa potentially makes them unresponsive to contemporary immune checkpoint inhibition. In this review, we highlight the hallmark events in the PCa tumor immune microenvironment and provide insights into the current state of knowledge in this field with a focus on the role of tumor cell intrinsic events that potentially regulate immune related events and determine therapeutic outcomes. We surmise that the cumulative impact of factors such as the pre-treatment immune status, PTEN expression, DNA damage repair gene mutations, and the effects of conventionally used treatments on the anti-tumor immune response should be considered in immunotherapy trial design in PCa.

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

“…Arguably, heterogeneity is one of the greatest benefits of this model, as most cell-based models are thought to be clonally selected due to genetic drift. As PCa is a multifocal heterogeneous disease the derivation of the bulk DVL3 population allows for research into PCa evolution in responses to treatment 24 . Tumours formed by the DVL3s maintained the heterogeneous CK8+/CK5+ glandular structures and regions of AR positivity, similar to the tumours from which they were derived.…”

“…Development of immune therapies as a method of harnessing the immune system's anti-tumour effects has recently gained traction 25 . Immune checkpoint inhibitors (ICI) have been used successfully to treat melanoma and bladder cancers; however, their impact on PCa is more limited 24 . Unlike melanoma and lung cancer, PCa has low levels of infiltrating CD8+ T cells 24 , 25 .…”

“…Unlike melanoma and lung cancer, PCa has low levels of infiltrating CD8+ T cells 24 , 25 . The immune microenvironment of PCa has been implicated in a number of other ways including: host physiological factors, DNA damage response defects, low levels of tumour-associated antigens and the association of these factors with PTEN loss 24 . PTEN loss occurs in 20% of primary PCa patients and has been associated with poorer overall survival 7 , 24 .…”

“…The immune microenvironment of PCa has been implicated in a number of other ways including: host physiological factors, DNA damage response defects, low levels of tumour-associated antigens and the association of these factors with PTEN loss 24 . PTEN loss occurs in 20% of primary PCa patients and has been associated with poorer overall survival 7 , 24 . Additionally, melanoma patients with PTEN loss also show lower levels of tumour infiltrating lymphocytes (TIL) 24 .…”

“…PTEN loss occurs in 20% of primary PCa patients and has been associated with poorer overall survival 7 , 24 . Additionally, melanoma patients with PTEN loss also show lower levels of tumour infiltrating lymphocytes (TIL) 24 . We have confirmed that this is also true in the DVL3 allografts, underscoring the more immuno-suppressed microenvironment of these tumours compared to the TRAMP-C1 tumours (Figure-2D).…”