CTLA-4 blockade enhances the CTL responses to the p53 self-tumor antigen.
p53 is an attractive target for cancer immunotherapy because it is overexpressed in a high proportion of many different types of tumors. However, it is also expressed in normal tissues and acts as a toleragen in vivo. Previously, detailed examination of the repertoire specific for the murine p53(261-269) epitope in conventional and p53-deficient mice demonstrated that because of expression of p53, the CD8(+) T cells that respond to this epitope express low-affinity TCRs. It has been reported that tolerance to tumor Ags can be broken by in vivo administration of anti-CTLA-4 mAb. With the goal of overriding tolerance and achieving optimal activation of p53-specific CTL, the current study has assessed the effect of anti-CTLA-4 mAb on the p53-specific repertoire. It was found that blockade of CTLA-4 engagement at the time of antigenic stimulation induced a vigorous amplification of the CTL responses to p53 as well as proportionate expansion of the memory T cell pool. This effect was dependent on the presence of CD4(+) T cell help and correlated with an enhancement of helper function. However, anti-CTLA-4 treatment did not enhance the avidity of the resultant p53-specific CTL populations and, therefore, could not reverse this important consequence of tolerance.
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
J
J
Hernández
A
A
Ko
L A
LA
Sherman
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D002478:Cells, Cultured; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D051381:Rats; D017634:Self Tolerance; D013234:Stem Cells / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000008:administration & dosage / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D000069594:Abatacept