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CTLA-4 blockade enhances the CTL responses to the p53 self-tumor antigen
J Hernández1, A Ko, L A Sherman
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
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.
Insights
Blocking CTLA-4 enhances cytotoxic T lymphocyte (CTL) responses to the tumor antigen p53 by amplifying CTL numbers and memory T cells. However, this approach does not increase the avidity of these cancer-fighting T cells.
Area of Science:
- Immunology
- Cancer Biology
- T cell immunology
Background:
- p53 is a tumor antigen overexpressed in many cancers, making it a target for immunotherapy.
- p53 is also present in normal tissues, inducing immune tolerance and low-affinity T cell responses.
- Immune tolerance to tumor antigens can be overcome by anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monoclonal antibody (mAb) treatment.
Purpose of the Study:
- To investigate the effect of anti-CTLA-4 mAb on p53-specific T cells.
- To determine if anti-CTLA-4 mAb can override tolerance and enhance p53-specific cytotoxic T lymphocyte (CTL) activation.
Main Methods:
- Assessment of p53-specific T cell repertoire in mice treated with anti-CTLA-4 mAb.
- Analysis of CTL responses, memory T cell pool expansion, and T cell avidity.
- Evaluation of CD4(+) T cell help in mediating anti-CTLA-4 mAb effects.
Main Results:
- Anti-CTLA-4 mAb blockade amplified CTL responses to p53 and expanded the memory T cell pool.
- The observed amplification was dependent on CD4(+) T cell help, which was enhanced by the treatment.
- Anti-CTLA-4 mAb treatment did not increase the avidity of the p53-specific CTLs.
Conclusions:
- Anti-CTLA-4 mAb can effectively boost anti-p53 CTL responses and memory formation, suggesting a potential immunotherapy strategy.
- The enhancement of T cell responses by anti-CTLA-4 mAb is mediated by improved CD4(+) T cell function.
- Despite increased CTL numbers, anti-CTLA-4 mAb does not overcome the low-avidity consequence of p53-induced tolerance.