Identification of the personalized repertoire of conventional and non-canonical tumor antigens
- Autores: María Lozano Rabella
- Directores de la Tesis: Josep Tabernero Caturla (dir. tes.), Alena Gros Vidal (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2022
- Idioma: inglés
- Tribunal Calificador de la Tesis: Dolores Jaraquemada Pérez de Guzmán (presid.), Luis Álvarez Vallina (secret.), Michal Bassani (voc.)
- Programa de doctorado: Programa de Doctorado en Inmunología Avanzada por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
The identification of tumor antigens is critical to better understand the immune response to tumors and to develop more effective cancer immunotherapies. Immunological screenings have frequently identified natural T-cell responses to conventional tumor antigens such as neoantigens, cancer-germline, and differentiation antigens in cancer patients. Recent evidence suggests that peptides derived from nonC proteins are specifically presented on HLA-I from tumor cells, thus expanding the repertoire of targetable tumor antigens. One of the main concerns is whether those nonC HLA-I ligands can naturally elicit T-cell responses and whether they are specifically presented by tumor cells, with important implications for designing therapeutic interventions.
In this thesis, we have studied in detail the personalized repertoire of tumor antigens recognized by tumor-reactive T cells in 9 cancer patients with distinct tumor histologies including conventional tumor antigens, but also expanding the scope to non-canonical tumor antigen sources.
In the first part, we investigated whether tumor-reactive T cells recognize conventional tumor antigens through three different methods including personalized neoantigen screening with TMG, in silico prediction and pHLA-I immunopeptidomics. However, the specific antigen/s targeted by the majority of tumor-reactive lymphocytes could not be determined. In the second part, we used a proteogenomics approach to identify peptides derived from non-canonical proteins presented on HLA-I of patient-derived TCL (nonC-TL). We frequently identified nonC-TL which were mainly derived from 5'UTR regions and represented the most abundant source of candidate tumor antigens. However, pre-existing T-cell responses targeting nonC-TL were not detected in any patient studied. In contrast, tumor-reactive lymphocytes consistently displayed preferential recognition of neoantigens and also recognized cancer-germline and tissue differentiation antigens. Nonetheless, we showed that nonC-TL can elicit de novo T-cell responses via in vitro sensitization of donor PBL. We identified TCR specific to three nonC-TL peptides, two of which mapped to the 5' UTR regions of HOXC13 and ZKSCAN1 genes, and one mapping to a non-coding spliced variant of C5orf22C gene. Importantly, we found that these immunogenic nonC-TL display therapeutic potential, as they were expressed across diverse tumor types, but were barely detected in healthy cells. Altogether, our results show that nonC-TL antigens hold great promise as new therapeutic targets as they can be immunogenic, are frequently presented on HLA-I of tumor cells, shared across patients, and barely expressed on healthy cells.
However, despite the extensive immunological screening performed including nonC-TL, neoantigens, cancer-germline, and melanoma-associated antigens, the specificity of many tumor-reactive lymphocytes remains unknown and warrants further investigation.
