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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1427424

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

Provisionally accepted
Silvia Brugiapaglia Silvia Brugiapaglia 1,2Sara Bulfamante Sara Bulfamante 1Claudia Curcio Claudia Curcio 1,2Maddalena Arigoni Maddalena Arigoni 1RaffaEle A. Calogero RaffaEle A. Calogero 1Lisa Bonello Lisa Bonello 1Elisa Genuardi Elisa Genuardi 1Rosella Spadi Rosella Spadi 3Maria Antonietta Satolli Maria Antonietta Satolli 3Donata Campra Donata Campra 4Daniele Giordano Daniele Giordano 1Paola Cappello Paola Cappello 1,2Francesca Cordero Francesca Cordero 5Francesco Novelli Francesco Novelli 1,2*
  • 1 Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
  • 2 Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, School of Medicine, University of Turin, Torino, Piedmont, Italy
  • 3 Centro Oncologico Ematologico Subalpino, Azienda Ospedaliera Universitaria Città della Salute e della Scienza, Torino, Italy, Turin, Piedmont, Italy
  • 4 SC Chirurgia Generale d'Urgenza e Pronto Soccorso, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy, Turin, Piedmont, Italy
  • 5 Department of Computer Science, University of Turin, Turin, Italy, Turin, Piedmont, Italy

The final, formatted version of the article will be published soon.

    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. Proliferation and cytokine release from PDA patient peripheral T lymphocytes, before and after CT, were analyzed in vitro in response to four tumorassociated antigens (TAA), namely ENO1, FUBP1, GAPDH and K2C8. 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 ENO1stimulated 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. These data suggest that the expression of fatty acid or IRAK1/IL1R-related 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.

    Keywords: Pancreatic Cancer, chemotherapy, Tumor-associated antigens, T lymphocyte response, Anti-tumor responses

    Received: 03 May 2024; Accepted: 15 Jul 2024.

    Copyright: © 2024 Brugiapaglia, Bulfamante, Curcio, Arigoni, Calogero, Bonello, Genuardi, Spadi, Satolli, Campra, Giordano, Cappello, Cordero and Novelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Francesco Novelli, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy

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