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

Front Immunol. 2024 Aug 8:15:1427424. doi: 10.3389/fimmu.2024.1427424. eCollection 2024.

Abstract

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.

Keywords: T lymphocyte response; anti-tumor responses; chemotherapy; pancreatic cancer; tumor-associated antigens.

MeSH terms

  • Aged
  • Antigens, Neoplasm* / genetics
  • Antigens, Neoplasm* / immunology
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / immunology
  • Carcinoma, Pancreatic Ductal* / therapy
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / immunology
  • Pancreatic Neoplasms* / therapy
  • Phosphopyruvate Hydratase / genetics
  • Phosphopyruvate Hydratase / immunology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transcriptome

Substances

  • Antigens, Neoplasm
  • Phosphopyruvate Hydratase
  • Receptors, Antigen, T-Cell

Associated data

  • figshare/10.6084/m9.figshare.25975231

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (IG no. 19931 to FN; IG no. 27020 to FN; 26341 to PC); Italian Ministry of Health-Progetti di Rilevante Interesse Nazionale (2022ELLA9L to FN; 2022TRSH52 to CC); European Union - Next Generation EU - PNRR M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (PNRR-POC-2022-12375658 to FN); Fondazione Compagnia di San Paolo-PoC Instruments (ID 116390 to PC); Italian Ministry of Foreign Affairs and International Cooperation (MAECI) (SG23GR04 to PC); Fondazione Ricerca Molinette Onlus (CD38 and Associazione Ursula e Giorgio Cytron); and the Fondazione Nadia Valsecchi; Rotaract, Distretto 2031.