Inducible expression of cancer-testis antigens in human prostate cancer

// Erika Heninger 1, 3 , Timothy E.G. Krueger 3 , Stephanie M. Thiede 1, 3 , Jamie M. Sperger 1, 3 , Brianna L. Byers 3 , Madison R. Kircher 3 , David Kosoff 1, 3 , Bing Yang 2, 3 , David F. Jarrard 2, 3 , Douglas G. McNeel 1, 3 , Joshua M. Lang 1, 3 1 Department of Medicine, University of Wisconsin, Madison, Madison, WI 53705, USA 2 Department of Urology, University of Wisconsin, Madison, Madison, WI 53705, USA 3 University of Wisconsin Carbone Cancer Center, Madison, Madison, WI 53705, USA Correspondence to: Joshua M. Lang, email: jmlang@medicine.wisc.edu Keywords: cancer testis antigen, prostate cancer, epigenetics, tumor immunotherapy, methylation Received: April 22, 2016      Accepted: October 11, 2016      Published: October 17, 2016 ABSTRACT Immune tolerance to self-antigens can limit robust anti-tumor immune responses in the use of tumor vaccines. Expression of novel tumor associated antigens can improve immune recognition and lysis of tumor cells. The cancer-testis antigen (CTA) family of proteins has been hypothesized to be an ideal class of antigens due to tumor-restricted expression, a subset of which have been found to induce antibody responses in patients with prostate disease. We demonstrate that CTA expression is highly inducible in five different Prostate Cancer (PC) cell lines using a hypomethylating agent 5-Aza-2′-deoxycytidine (5AZA) and/or a histone deacetylase inhibitor LBH589. These CTAs include NY-ESO1, multiple members of the MAGE and SSX families and NY-SAR35. A subset of CTAs is synergistically induced by the combination of 5AZA and LBH589. We developed an ex vivo organ culture using human PC biopsies for ex vivo drug treatments to evaluate these agents in clinical samples. These assays found significant induction of SSX2 in 9/9 distinct patient samples and NY-SAR35 in 7/9 samples. Further, we identify expression of SSX2 in circulating tumor cells (CTC) from patients with advanced PC. These results indicate that epigenetic modifying agents can induce expression of a broad range of neoantigens in human PC and may serve as a useful adjunctive therapy with novel tumor vaccines and checkpoint inhibitors.