Epigenetic Modulation to Enable Antigen-specific T-cell Therapy of Colorectal Cancer

Abstract

Development of specific immunotherapy for colorectal cancer (CRC) will require identification of antigens selectively or exclusively expressed on CRC cells and strategies to induce and enhance immune responses against these antigenic targets. Cancer-testis (C-T) antigens are proving to be excellent targets for immunotherapy of solid tumors such as melanoma, but their clinical utility for treatment of CRC has to date been limited by their infrequent expression in CRC cells. Here we report that the hypomethylating agent 5-aza-2′-deoxycytidine (DAC) induces expression of NY-ESO-1 and other C-T genes in CRC cells both in vitro and in vivo in a dose-dependent manner but has negligible effects on the expression of C-T genes in normal non-transformed cells such as fibroblasts. The induction by DAC of NY-ESO-1 expression in CRC cells persists over 100 days after DAC exposure and is associated with increased levels of NY-ESO-1 protein. CRC cells exposed to DAC at concentrations that can be readily achieved in vivo are rendered susceptible to MHC-restricted recognition by CD8+ NY-ESO-1-specific T cells. We also demonstrate that retroviral transduction of polyclonal peripheral blood T cells from a metastatic CRC patient with the T cell receptor (TCR) α and β chain genes encoding an HLA-A2-restricted, NY-ESO-1157-165-specific TCR can be used to generate both CD8+ and CD4+ NY-ESO-1157-165-specific T cells that selectively recognize DAC-treated CRC but not non-transformed cells. Collectively, these results suggest that the combination of epigenetic modulation and adoptive transfer of genetically engineered T lymphocytes may enable specific immunotherapy of CRC.

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

“…Therefore, a decreased cell index indicates loss of viable target tumor cells. This is an established quantitative real-time method for assessing antigen-dependent CTL activity (35–37) Cells were plated at a 1:5 T/E ratio, which yielded optimal cytotoxic activity (supplemental Fig. 2A).…”

Decitabine reactivated pathways in platinum resistant ovarian cancer

“…In all patients' biopsies, decitabine treatment markedly (P<0.01) altered methylation of CATG1B cancer/testis antigen 1B ( NY-ESO-1 ) (Supplemental Figure S2), a target antigen for immunotherapy [21], suggesting a dual role of decitabine as an epigenetic modulator and possible immunosensitizer. Although a vaccine target in OC, limited NY-ESO-1 expression represents a barrier to vaccine efficacy, and decitabine-mediated upregulation of NY-ESO-1 has the potential to augment this therapeutic approach [22].…”

CAR T Cells for Solid Tumors

“…57 Systemic administration of antagonists (blocking antibodies) to these co-inhibitory receptors resulted in remarkable response rates even in refractory solid tumors, 58-60 and combining blocking antibodies with CAR T cells should boost antitumor effects. Other strategies include epigenetic modifiers that upregulate the expression of tumor associated antigens 61 or the use of targeted therapies that inhibit tumor cells growth, but are not detrimental to T cells. 62 …”