Human preprocalcitonin self-antigen generates TAP-dependent and -independent epitopes triggering optimised T-cell
Aurélie Durgeau1,2, Yasemin Virk1, Gwendoline Gros1
1INSERM UMR 1186, Integrative Tumour Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Fac. de Médecine, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
Abstract:
Tumours often evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes associated with impaired peptide processing are immunogenic non-mutated neoantigens that emerge during tumour immune evasion. The preprocalcitonin (ppCT)16-25 neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expression of TAP and frequently express ppCT self-antigen. We also show that ppCT includes HLA-A2-restricted epitopes that are processed by TAP-independent and -dependent pathways. Processing occurs in either the endoplasmic reticulum, by signal peptidase and signal peptide peptidase, or in the cytosol after release of a signal peptide precursor or retrotranslocation of a procalcitonin substrate by endoplasmic-reticulum-associated degradation. Remarkably, ppCT peptide-based immunotherapy induces efficient T-cell responses toward antigen processing and presenting machinery-impaired tumours transplanted into HLA-A*0201-transgenic mice and in NOD-scid-Il2rγnull mice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for treatment of tumours that have escaped immune recognition.
Insights
Tumours evade immune responses by downregulating TAP, leading to neoantigens like preprocalcitonin (ppCT). Immunotherapy targeting ppCT effectively combats these immune-evading tumours, offering a new treatment strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumours frequently evade CD8 T-cell immunity by downregulating the transporter associated with antigen processing (TAP).
- This evasion mechanism leads to the emergence of immunogenic non-mutated neoantigens arising from impaired peptide processing.
- The preprocalcitonin (ppCT)16-25 neoepitope exemplifies this class of antigens.
Purpose of the Study:
- To investigate the expression of TAP and ppCT in human lung tumours.
- To elucidate the processing pathways of ppCT-derived epitopes.
- To evaluate the therapeutic potential of ppCT peptide-based immunotherapy against tumours with impaired antigen processing.
Main Methods:
- Analysis of TAP expression in human lung tumours.
- Identification and characterization of HLA-A2-restricted ppCT epitopes.
- Investigation of TAP-dependent and -independent processing pathways involving endoplasmic reticulum and cytosolic mechanisms.
- Assessment of ppCT peptide-based immunotherapy in mouse models (HLA-A*0201-transgenic and NOD-scid-Il2rγnull mice with human PBMC transfer).
Main Results:
- Most human lung tumours exhibit altered TAP expression and frequently express the ppCT self-antigen.
- ppCT contains HLA-A2-restricted epitopes processed through both TAP-dependent and -independent pathways.
- These pathways involve signal peptidases in the endoplasmic reticulum or cytosolic degradation/retrotranslocation mechanisms.
- ppCT peptide-based immunotherapy successfully induced T-cell responses against tumours with impaired antigen processing machinery in preclinical models.
Conclusions:
- ppCT is a relevant neoantigen in tumours with immune evasion mechanisms.
- ppCT epitopes can be processed independently of TAP, offering therapeutic opportunities.
- ppCT-specific T lymphocytes represent a promising therapeutic strategy for treating tumours that have escaped immune surveillance.
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