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.
Highlights
Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men; each year, ∼220,000 men in the United States are diagnosed with prostate cancer (PCa) [3]
We focus on the immune features associated with localized and metastatic PCa to allow a knowledge-driven approach for future immunotherapybased treatments
In addition to the presence of immunosuppressive lymphocytes, multiple reports have demonstrated that high tumor-associated macrophage (TAM) infiltration in the PCa tumor immune microenvironment (TIME) is pro-tumorigenic [31], most do not differentiate between the M1 and M2 phenotypes of TAMs
Summary
Natasha Vitkin 1, Sarah Nersesian 1,2, David Robert Siemens 1,3 and Madhuri Koti * 1,2,3,4. 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. 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.
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