MC32 tumor cells acquire Ag-specific CTL resistance through the loss of CEA in a colon cancer model

Abstract

We previously reported that MC32 cells resist carcinoembryonic antigen (CEA) DNA vaccination by losing their antigen presentation to Ag-specific CTLs in the context of MHC class I antigens in a colon cancer therapeutic model. In this study, we selected 2 tumor cells, MC32-S2-2 and MC32-S4-2, which have the ability to form tumors in CEA DNA vaccine-immunized mice. Wild type MC32 cells grew significantly less in CEA-immunized mice (with Ag-specific CTL lytic activity) than in control mice (with no Ag-specific CTL lytic activity). However, MC32-S2-2 and MC32-S4-2 cells grew at a similar rate in both control and CEA-immunized mice, confirming their resistant status against CEA DNA vaccination. MC32-S2-2 and MC32-S4-2 cells were not susceptible to lysis by CEA-specific CD8+ T cells. Moreover, when MC32-S2-2 and MC32-S4-2 cells were used as stimulating agents of CEA-specific immune cells for IFN-γ production, these cells failed to stimulate the induction of Ag-specific IFN-γ, suggesting a loss of tumor cell recognition by Ag-specific immune cells. However, MC32-S2-2 and MC32-S4-2 cells expressed MHC class I antigens in a manner similar to that of wild type MC32 cells. Finally, Western blot assay confirmed that in MC32-S2-2 and MC32-S4-2 cells, CEA expression remained absent but mouse CEA was expressed. Taken together, these data show that MC32 cells may also be able to achieve resistance to CEA-specific CTLs by antigen loss in this model.

Regulation of the translation activity of antigen-specific mRNA is responsible for antigen loss and tumor immune escape in a HER2-expressing tumor model

“…Moreover, a lack of HER2 protein expression was further confirmed by Western blot and IFN-γ release assays, as well as ELISA. These results, showing antigen loss as a way to evade antitumor immunity, are in agreement with our recent observation in a MC32 prophylactic tumor model 15 . Contrary to this, antigen loss was not associated with tumor immune evasion in the MC32 and CT26/HER2 therapeutic tumor models 9,12 .…”

“…Despite this, numerous evidence has shown that tumor cells counter antitumor CTL immunity by losing their antigen or MHC class I molecules 13,14 . Similar to this, we also observed that tumor cells acquired Ag-specific CTL resistance through the loss of tumor antigen in the MC32 tumor prophylactic model 15 . In the MC32 tumor therapeutic model, on the other hand, tumor cells acquired CTL resistance through losing antigen presentation in conjunction with MHC class I molecules 12 .…”

Multi-target chimaeric VLP as a therapeutic vaccine in a model of colorectal cancer

“…These therapies target a single antigen, such as carcinoembryonic antigen (CEA), a TAA normally found expressed at low levels throughout the intestinal mucosa [ 6 ] and overexpressed in the majority of adenocarcinomas originating in either the colon or rectum [ 7 ]. Although CEA is a known target for therapeutic vaccination in CRC, expression of CEA may not be consistent throughout the heterogeneous tumour mass, and expression can be reduced following targeted vaccination [ 8 , 9 ].…”

DNA vaccines 2014 meeting: Highlights and overview

“…In this report entitled "MC32 tumor cells acquire Ag-specific CTL resistance through the loss of CEA in a colon cancer model" Lee and Sin demonstrated that MC32 (murine colon adenocarcinoma) cells likely were able to acquire resistance to CEA specific CTLs, generated by a DNA vaccine, through antigen loss 16 . This finding indicated that this process might have an overall general role in resistance of cancers to DNA as well as conventional immune based therapies.…”