| Title: |
In pancreatic cancer patients, chemotherapy reshapes the gene expression profile and antigen receptor repertoire of T lymphocytes and enhances their effector response to tumor-associated antigens |
| Authors: |
Brugiapaglia, Silvia; Bulfamante, Sara; Curcio, Claudia; Arigoni, Maddalena; Calogero, Raffaele; Bonello, Lisa; Genuardi, Elisa; Spadi, Rosella; Satolli, Maria Antonietta; Campra, Donata; Giordano, Daniele; Cappello, Paola; Cordero, Francesca; Novelli, Francesco |
| Source: |
Frontiers in Immunology ; volume 15 ; ISSN 1664-3224 |
| Publisher Information: |
Frontiers Media SA |
| Publication Year: |
2024 |
| Collection: |
Frontiers (Publisher - via CrossRef) |
| Description: |
Introduction Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 13%. Less than 20% of patients have a resectable tumor at diagnosis due to the lack of distinctive symptoms and reliable biomarkers. PDA is resistant to chemotherapy (CT) and understanding how to gain an anti-tumor effector response following stimulation is, therefore, critical for setting up an effective immunotherapy. Methods Proliferation, and cytokine release and TCRB repertoire of from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumor-associated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. Transcriptional state of PDA patient PBMC was investigated using RNA-Seq before and after CT. Results CT increased the number of TAA recognized by T lymphocytes, which positively correlated with patient survival, and high IFN-γ production TAA-induced responses were significantly increased after CT. We found that some ENO1-stimulated T cell clonotypes from CT-treated patients were expanded or de-novo induced, and that some clonotypes were reduced or even disappeared after CT. Patients that showed a higher number of effector responses to TAA (high IFN-γ/IL-10 ratio) after CT expressed increased fatty acid-related transcriptional signature. Conversely, patients that showed a higher number of regulatory responses to TAA (low IFN-γ/IL-10 ratio) after CT significantly expressed an increased IRAK1/IL1R axis-related transcriptional signature. Conclusion These data suggest that the expression of fatty acid or IRAK1/IL1Rrelated genes predicts T lymphocyte effector or regulatory responses to TAA in patients that undergo CT. These findings are a springboard to set up precision immunotherapies in PDA based on the TAA vaccination in combination with CT. |
| Document Type: |
article in journal/newspaper |
| Language: |
unknown |
| DOI: |
10.3389/fimmu.2024.1427424 |
| DOI: |
10.3389/fimmu.2024.1427424/full |
| Availability: |
https://doi.org/10.3389/fimmu.2024.1427424; https://www.frontiersin.org/articles/10.3389/fimmu.2024.1427424/full |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.192A83C5 |
| Database: |
BASE |