T cell coinhibition in prostate cancer: new immune evasion pathways and emerging therapeutics

Abstract

T cell-mediated adaptive immune response is controlled by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 family and their receptor CD28 family. Coinhibition is exploited by prostate cancer as an immune evasion pathway. Overexpression of coinhibitory B7x and B7-H3 in prostate cancer correlates with poor disease outcome, whereas tumor-infiltrating immune cells have enhanced expression of PD-L1 and its receptor PD-1. New insights into the complex mechanisms governing B7 expression in the tumor microenvironment have been reported and therapies aimed at overcoming T cell coinhibition with antagonistic monoclonal antibodies are emerging as effective tumor immunotherapies. Therapies that block B7x and B7-H3, either as monotherapies or in synergism with traditional therapies, should be pursued.

Figure 1. T cell coinhibition is exploited by prostate cancer as immune evasion pathways

T cell coinhibitory B7 family members B7x and B7-H3 are overexpressed by prostate cancer cells as revealed by immunohistochemical staining. Tissue microarrays of human prostate cancer were stained with antibodies against B7-H3 (left) or B7x (right). B7-H3 and B7x bind unidentified receptors on activated T cells to downregulate TCR-mediated signaling, which might contribute to poor clinical outcome. In addition, many prostate cancer patients have soluble B7 molecules in the blood, but the mechanism of production and the function of soluble B7 are currently unknown

Figure 2. Regulatory mechanisms of PD-L1 and B7-H3 expression

The PD-L1 promoter has binding sites for transcription factors IRF-1 and NF-κB, so IFN-γ-mediated signaling through the JAK/STAT-1/IRF-1 pathway and TLR ligand-mediated signaling through the MEK/ERK/NF-κB pathway can upregulate PD-L1 gene transcription. Signaling through the PI3K/Akt/mTOR pathway, usually inhibited by PTEN, can activate S6K1, which regulates the 5′ UTR of PD-L1. This results in recruitment of PD-L1 transcripts to polysomes and associated PD-L1 translation. By contrast, miR-513, which can be inhibited by IFN-γ signaling, prevents PD-L1 translation by binding to the PD-L1 3′ UTR. B7-H3 expression can also be enhanced by IFN-γ signaling, perhaps through blocking miR-29, which otherwise represses B7-H3 translation. It seems that different types of cells use overlapping yet divergent pathways to regulate the expression of PD-L1 and B7-H3.

Figure 3. Blockade of T cell coinhibition as an emerging therapeutic approach for prostate cancer

APCs (light blue) take up antigens (red circles) released from tumor cells and present them to T cells (pink) in the context of B7-1 and B7-2 costimulation. Tumor cells (orange) can also present tumor antigens to T cells in the absence of costimulation. Upon T cell activation, CTLA-4 and PD-1 are expressed and inhibit immune responses. Therefore, specific blockade of CTLA-4, leaving TCR and CD28 signaling intact, enhances antitumor immunity. Blockade of CTLA-4 on Tregs (blue) might also reduce Treg-mediated immunosuppression. Immune cells infiltrating prostate cancer have enhanced expression of PD-L1 and PD-1. Therefore immunotherapies blocking the PD-1/PD-L1 pathway are being tested. Finally, both B7x and B7-H3 inhibit T cell functions and are overexpressed by many human cancers including prostate cancer. Consequently, blockade of tumor associated B7-H3 and B7x could be another attractive approach in tumor immunotherapy.