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.
Highlights
While often described as an indolent or treatable disease, prostate cancer (PC) remains the most common cancer and second leading cause of cancer-related death in US men, as well as the cause of considerable morbidity
We demonstrate that cancer-testis antigen (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
We evaluated 29 CTAs that had previously been identified in patients with prostate disease using antibody screening methodology and may be immunologically relevant in prostate cancer (Table 1) [37,38,39,40, 46, 47]
Summary
While often described as an indolent or treatable disease, prostate cancer (PC) remains the most common cancer and second leading cause of cancer-related death in US men (www.cdc.gov/uscs), as well as the cause of considerable morbidity. Recent advances in immunotherapies, including anti-cancer vaccines (prostate cancer) [3] and checkpoint inhibitors (melanoma, lung and renal cancers) [4,5,6] have been shown to improve survival for patients with advanced disease. These therapies rely on the expression of tumor-associated antigens (TAAs) in the context of MHC class I for a CD8 T cell mediated anti-tumor immune response [7]. Classical PC antigens currently in clinical trials include prostate specific antigen (PSA), prostatic acid phosphatase (PAP), androgen receptor (AR) and prostatespecific membrane antigen (PSMA) (NCT00583752, NCT00849121, NCT00694551)
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