Abstract 1437: Prostate cancer cells up-regulate PD-L1 in response to pro-inflammatory cytokines.
Authors: Boikos Sosipatros A. , Nirschl Chris , Martin Allison , Alme Angela , Harris Timothy , Drake Charles G. 
Published: August 2014

In the last few years, the approval of two novel agents for advanced cancer, the anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody ipilimumab for patients with metastatic melanoma and the antigen presenting cell-based product sipuleucel-T for patients with castration-resistant prostate cancer, have transformed the field of immunotherapy. Knowing that cancer cells are continuously evolving due to genetic and epigenetic variability, it makes sense to attempt to eliminate the tumor cells using targeted antitumor immune responses, especially in prostate cancer where several studies have demonstrated infiltration of tumors with CD4 and CD8 T cells. Among the different mechanisms responsible for the failure of the immune system to develop a durable response towards tumors, the expression of immune checkpoint molecules on tumor infiltrating CD8 (killer) T cells has been shown to have a crucial role by suppressing CD8 T cell function. The PD-1 / B7-H1 pathway has recently emerged as a key player in this process, since single-agent blockade of PD-1 or PD-L1 has resulted in sustained responses in patients with renal cell carcinoma, melanoma and lung cancer. However, PD1 or PD-L1 blockade in prostate cancer have not had the same results and based on previously limited immunohistochemistry data, there is low expression of PD-L1 at prostate cancer samples. In our study,surprisingly, we were able to modify the immune checkpoint expression after treatment with cytokines known to be modulated by either vaccination or androgen deprivation. We tested a number of prostate cancer cell lines (LnCap, LnCap-C42B, LnCap-ABL, LAPC4, VCap, DU145, PC3, CWR22R and E006AA) for PD-L1, PD-L2, MHCII and B7-H3 expression by flow cytometry, either at baseline or after treatment for 48 hours with IFNγ, IL6, IL8, IL10 or TGFβ. At baseline, PD-L1, PD-L2, MHCII and B7-H3 was detected by flow cytometry in 4, 1, 2, and 6 of the cell lines respectively. When we treated the cell lines with IFNγ, 4 of them showed a robust up-regulation of PD-L1 while surprisingly several other cell lines up-regulated PD-L2, MHC-II and B7H3. Treatment with IL6, IL8 and IL10 and TGFβ was able to up-regulate PD-L1 in several cell lines. In this study we were able to show for the first time in prostate cancer regulation of immune checkpoints by IFNγ, IL6, IL8, IL10 and TGFβ. These data argue for a combinatorial approach, in which initially cytokines, regulated through an anti-tumor vaccine or androgen deprivation, sensitize the prostate cancer cells to immune response through alteration in expression of the immune checkpoints and subsequently this immune response is sustained by blocking the PD-1 / B7-H1 pathway.

Citation Format: Sosipatros A. Boikos, Chris Nirschl, Allison Martin, Angela Alme, Timothy Harris, Charles G. Drake. Prostate cancer cells up-regulate PD-L1 in response to pro-inflammatory cytokines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1437. doi:10.1158/1538-7445.AM2013-1437