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A novel category of antigens enabling CTL immunity to tumor escape variants: Cinderella antigens
Ursula J E Seidel1, Claudia C Oliveira, Margit H Lampen
1Department of Clinical Oncology, K1-P, Leiden University Medical Center, Albinusdreef 2, 2333 Leiden, The Netherlands.
Abstract:
Deficiencies in MHC class I antigen presentation are a common feature of tumors and allows escape from cytotoxic T lymphocyte (CTL)-mediated killing. It is crucial to take this capacity of tumors into account for the development of T-cell-based immunotherapy, as it may strongly impair their effectiveness. A variety of escape mechanisms has been described thus far, but progress in counteracting them is poor. Here we review a novel strategy to target malignancies with defects in the antigenic processing machinery (APM). The concept is based on a unique category of CD8+ T-cell epitopes that is associated with impaired peptide processing, which we named TEIPP. We characterized this alternative peptide repertoire emerging in MHC-I on tumors lacking classical antigen processing due to defects in the peptide transporter TAP (transporter associated with peptide processing). These TEIPPs exemplify interesting parallels with the folktale figure Cinderella: they are oppressed and neglected by a stepmother (like functional TAP prevents TEIPP presentation), until the suppression is released and Cinderella/TEIPP achieves unexpected recognition. TEIPP-specific CTLs and their cognate peptide-epitopes provide a new strategy to counteract immune evasion by APM defects and bear potential to targeting escape variants observed in a wide range of cancers.
Insights
Tumors evade immune attack by disabling antigen presentation. A novel strategy identifies unique T-cell epitopes (TEIPPs) that can overcome these defects, offering new cancer immunotherapy approaches.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Tumors frequently exhibit deficiencies in MHC class I antigen presentation, enabling immune evasion via cytotoxic T lymphocyte (CTL) resistance.
- Impaired antigen processing machinery (APM) is a significant hurdle for effective T-cell-based cancer immunotherapies.
- Existing strategies to overcome tumor immune evasion related to APM defects have shown limited success.
Purpose of the Study:
- To review a novel immunotherapy strategy targeting malignancies with defective APM.
- To introduce and characterize a unique class of CD8+ T-cell epitopes, termed TEIPPs (impaired peptide processing), associated with APM defects.
- To explore the potential of TEIPP-specific T-cells in overcoming tumor immune evasion.
Main Methods:
- Review of existing literature on MHC class I antigen presentation and tumor immune evasion.
- Characterization of alternative peptide repertoires (TEIPPs) presented by tumors with defects in the transporter associated with peptide processing (TAP).
- Analysis of TEIPP-specific CD8+ T-cell responses and their recognition of tumor cells.
Main Results:
- Defects in TAP lead to the presentation of a unique repertoire of peptides (TEIPPs) on MHC-I.
- TEIPPs represent an alternative antigen source for T-cell recognition in tumors with impaired classical antigen processing.
- TEIPP-specific CTLs demonstrate potential for targeting cancer cells that evade immune surveillance through APM defects.
Conclusions:
- TEIPPs offer a promising new avenue for developing immunotherapies against cancers with APM defects.
- Targeting TEIPPs can overcome immune escape mechanisms employed by tumors lacking functional TAP.
- This strategy holds potential for treating a broad spectrum of cancers exhibiting immune evasion via APM deficiencies.
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