Cancer antigen-specific cytotoxic T cells (CTLs) are very efficient at destroying cancer cells. However, large established tumors are very difficult to control by CTL adoptive therapy due to the genetic instability of cancer cells, which often results in the selection of variant cancer cells that can escape CTL destruction. Thus, targeting genes/molecules that contribute to genetic instability combined with CTL therapy should yield a better outcome for CTL adoptive therapy of cancer. Recently, activation induced cytidine deaminase (AID) has been identified to be an essential enzyme to regulate class switch recombination (CSR), somatic hypermutation (SHM) of the immunoglobulin gene in B cells. Interestingly, AID also targets other genetic targets. Thus, AID may serve as an active gene mutator in the whole genome and contribute to genetic instability. Using transgenic T cells specific for a natural tumor rejection antigen P1A (P1CTL) to treat mice with large established plasmacytoma J558 tumors, we found that P1CTL selected high numbers of mutations in the P1A antigenic epitope, known as antigenic drift. Since J558 is of B-cell lineage and constitutively expresses AID, it is of interest to know whether AID targets P1A and is involved in P1A antigenic drift, and whether targeting AID can prevent antigenic drift. This proposal contains two specific aims.
Specific aim 1. We have generated AID-disrupted J558 cells by RNA interference. We will determine whether different levels of AID mRNA expression correlate with tumor rejection rate by P1 CTL, and If so, is it due to reduced mutation rates? We will also determine whether forced expression of AID in AID- tumor cells (Meth A and P815) confer antigenic drift to these cells.
Specific aim 2. We will determine whether inhibition of cytidine deaminase by Tetrahydrouridine plus CTL adoptive therapy can eliminate large established tumors and prevent antigenic drift. If confirmed, targeting AID may represent an interesting approach for immunotherapy of AID+ tumors, such as many lineages of B cell lymphomas. ? ?
| Liu, Jin-Qing; Joshi, Pramod S; Wang, Chuansong et al. (2010) Targeting activation-induced cytidine deaminase overcomes tumor evasion of immunotherapy by CTLs. J Immunol 184:5435-43 |
| Liu, Jin-Qing; Bai, Xue-Feng (2008) Overcoming immune evasion in T cell therapy of cancer: lessons from animal models. Curr Mol Med 8:68-75 |
| Bai, Xue-Feng; Liu, Jin-Qing; Joshi, Pramod S et al. (2006) Different lineages of P1A-expressing cancer cells use divergent modes of immune evasion for T-cell adoptive therapy. Cancer Res 66:8241-9 |
