Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy

Background We previously found that PD-L1 expression is increased on tumor cells following vaccination treatments that lead to increased tumor-specific T cells that secrete IFN gamma. Indoleamine 2,3-dioxygenase (IDO) is another IFN gamma inducible gene that has potent immunosuppressive effects. There have been reports of IDO expression in prostate cancer; however, it is unknown whether IDO expression might similarly increase in prostate tumors following T-cell-based immunotherapy. Methods Blood samples from normal male blood donors (n = 12) and patients with different stages of prostate cancer (n = 89), including patients with metastatic, castration-resistant prostate cancer treated with a DNA vaccine and/or pembrolizumab, were evaluated for IDO activity by kynurenine and tryptophan levels. Metastatic tissue biopsies obtained pre- and post-treatments were evaluated for IDO expression. IDO suppression of vaccine-induced T-cell function was assessed by ELISPOT. Results Overall, IDO activity was increased in patients with more advanced prostate cancer. This activity, and IDO expression as detected immunohistochemically, increased following treatment with either a DNA vaccine encoding the prostatic acid phosphatase (PAP) tumor antigen or PD-1 blockade with pembrolizumab. Increased IDO activity after treatment was associated with the absence of clinical effect, as assessed by lack of PSA decline following treatment. Increased antigen-specific T-cell response, as measured by IFN gamma release, to the vaccine target antigen was detected following in vitro stimulation of peripheral blood cells with 1-methyltryptophan. Conclusions These findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition.