Major Histocompatibilty Complex-Restricted Adaptive Immune Responses to CT26 Colon Cancer Cell Line in Mixed Allogeneic Chimera

Abstract

Background. Although the induction of mixed allogeneic chimera shows promising clinical tolerance results in organ transplantation, its clinical relevance as an anti-cancer therapy is yet unknown. We introduced a mixed allogenic chimera setting with the use of a murine colon cancer cell line, CT26, by performing double bone marrow transplantation. Methods. We analyzed donor- and recipient-restricted anti-cancer T-cell responses, and phenotypes of subpopulations of T cells. The protocol involves challenging 1 x 10(5) cells of CT26 cells intra-hepatically on day 50 after bone marrow transplantation, and, by use of CT26 lysates and an H-2L(d)-restricted AH1 pentamer, flow cytometric analysis was performed to detect the generation of cancer-specific CD4(+) and CD8(+) T cells at various time points. Results. We found that immunocompetence against tumors depends heavily on cancer specific CD8(+) T-cell responses in a major histocompatibility complex-restricted manner; the evidence was further supported by the increase of interferon-gamma-secreting CD4(+) T cells. Moreover, we demonstrated that during the effector immune response to CT26 cancer challenge, there was a presence of central memory cells (CD62L(hi)CCR7(+)) as well as effector memory cells (CD62L(lo)CCR7(-)). Moreover, mixed allogeneic chimeras (BALB/c to C56BL/6 or vice versa) showed similar or heightened immune responses to CT26 cells compared with that of wild-type mice. Conclusions. Our results suggest that the responses of primary immunocompetency and of pre-existing memory T cells against allogeneic cancer are sustained and preserved long-term in a mixed allogeneic chimeric environment.