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Avoiding tolerance against prostatic antigens with subdominant peptide epitopes
M E Grossmann1, T Davila, T Celis
1Department of Urology, Mayo Clinic/Foundation, Rochester, Minnesota 55905, USA. grossmann.michael@mayo.edu
Abstract:
A potential novel therapy for prostate cancer is the induction of immune responses to normal prostate-associated antigens (PAA). One approach is to use synthetic peptides from PAA to educate T cells as a means of developing a defined and specific immunotherapy for prostate cancer. A likely major hurdle when using normal PAA for this type of therapy is the tolerance that the immune system may already have for PAA. To evaluate mechanisms for overcoming tolerance, the authors assessed the level of tolerance to SV40T antigen in a transgenic mouse. The SV40T antigen is selectively expressed in the prostates of mice from the transgenic adenocarcinoma mouse prostate (TRAMP) model. The authors have shown that TRAMP mice are tolerant to a dominant cytotoxic T-lymphocyte (CTL) epitope from the SV40T antigen compared with nontransgenic littermates. The tolerance was exhibited as early as 4 weeks and as late as 24 weeks. The use of multiple injections of an oligonucleotide that contains an unmethylated CpG induced high levels of hematopoiesis but did not overcome the tolerance. Injection of an antibody to activate CD40 increased the CTL response in normal mice but also did not overcome tolerance. However, tolerance in the TRAMP mice was avoided when an epitope that had previously been characterized as a subdominant epitope was administered. The authors are investigating the potential of subdominant epitopes to induce prostatitis and antitumor responses. The results of this work should facilitate the development of immune-based therapies for prostate cancer.
Insights
Overcoming immune tolerance to prostate-associated antigens (PAA) is key for cancer immunotherapy. Subdominant epitopes, not dominant ones, successfully induced immune responses in a mouse model, offering a promising strategy for prostate cancer treatment.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Prostate cancer immunotherapy aims to induce immune responses against prostate-associated antigens (PAA).
- Pre-existing immune tolerance to PAA poses a significant challenge for developing effective immunotherapies.
- The transgenic adenocarcinoma mouse prostate (TRAMP) model expresses SV40T antigen in the prostate, serving as a model for studying tolerance.
Purpose of the Study:
- To evaluate mechanisms for overcoming immune tolerance to PAA in the context of prostate cancer immunotherapy.
- To assess the immunogenicity of dominant and subdominant epitopes of SV40T antigen in TRAMP mice.
Main Methods:
- Assessed immune tolerance to SV40T antigen in TRAMP mice compared to nontransgenic littermates.
- Administered CpG oligonucleotides and anti-CD40 antibodies to evaluate their ability to overcome tolerance.
- Tested the immunogenicity of a subdominant epitope of SV40T antigen in TRAMP mice.
Main Results:
- TRAMP mice exhibited tolerance to a dominant cytotoxic T-lymphocyte (CTL) epitope of SV40T antigen from 4 to 24 weeks of age.
- CpG oligonucleotides induced hematopoiesis but did not overcome tolerance.
- Anti-CD40 antibody increased CTL response in normal mice but failed to overcome tolerance in TRAMP mice.
- Administration of a subdominant epitope successfully circumvented tolerance in TRAMP mice.
Conclusions:
- Immune tolerance to dominant PAA epitopes is a significant barrier in prostate cancer immunotherapy.
- Subdominant epitopes hold potential for inducing anti-tumor immune responses and overcoming tolerance.
- Further investigation into subdominant epitopes could facilitate the development of novel immune-based therapies for prostate cancer.