Inducible expression of cancer-testis antigens in human prostate cancer

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.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…Like in other tumor models mentioned above, decitabine was also demonstrated to induce the expression of CTAs in PCa, in a synergistic combination with the HDAC inhibitor panobinostat [149]. In this study, the authors created an ex vivo culture system of PCa biopsies, which further showed inducing of CTAs, namely SSX2, in all nine cultured specimens (originating from 9 different patients).…”

“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in PCa is depicted in Table 3 [108,[141][142][143][144][145][146][147][148][149][150][151][152]. Some studies have focused on epigenetic regulation of response to IFN, where both methylation and acetylation can be involved, as demonstrated by Dunn and collaborators [141].…”

Conjugation of TLR7 Agonist Combined with Demethylation Treatment Improves Whole-Cell Tumor Vaccine Potency in Acute Myeloid Leukemia

“…It has been found that TLR7 agonist (TLR7a) can be used in combination with chemotherapy, radiotherapy, and other immunotherapies to increase the immune response and to induce tumor cell apoptosis [24,25]. For example, a well-characterized TLR7 agonist R848, also called resiquimod, has been demonstrated that it works as an antitumor reagent in a mouse model of lymphoma when combined with radiation by priming antitumor immune response [26]. Our lab has previously synthesized an effective TLR7 agonist, SZU-101 [27,28], which also showed antitumor activity in a murine model of T cell lymphoma.…”

“…Total RNA was extracted from DAC-treated or untreated cells using Trizol reagent (Thermo Scientific, #15596026, USA) according to the 'manufacturer's instruction. RT was performed using the Reverse Transcription System (Promega, #A3500, USA) on 1 mg of total RNA, and PCR amplifications were then performed using primers shown in Table 1 [26]. Simultaneous amplification of β-actin was used as an internal control for the amount and integrity of the RNA analyzed.…”

Trial watch: DNA-based vaccines for oncological indications

“…One method to boost antigen presentation is to introduce specific point mutations in the sequence of the antigenic epitope, resulting in improved binding to MHC Class I molecules or the T-cell receptor (TCR). 138 Along these lines, the antitumor activity of a plasmid encoding mutated SSX family member 2 (SSX2; a TAA relevant for prostate carcinoma) [139][140][141] was studied in mice bearing an HLA-A2-expressing neoplasm engineered to express SSX2. Contrary to predictions, this DNA-based vaccine had limited immunostimulatory properties and poor efficacy, which was associated with increased expression of the immunosuppressive receptor programmed cell death 1 (PDCD1; best known as PD-1) on CD8 C T cells.…”