The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling

Maria Perez-Penco, Mikkel Byrdal, Lucia Lara de la Torre, Marta Ballester, Shawez Khan, Majken Siersbæk, Inés Lecoq, Cecilie Oelvang Madsen, Julie Westerlin Kjeldsen, Inge Marie Svane, Morten Hansen, Marco Donia, Julia Sidenius Johansen, Lars Rønn Olsen, Lars Grøntved, Inna Markovna Chen, Luis Arnes, Morten Orebo Holmström, Mads Hald Andersen*

*Corresponding author for this work

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Abstract

Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.

Original languageEnglish
Article number104659
JournalCellular and Molecular Immunology
Volume22
Issue number1
Pages (from-to)111-126
Number of pages16
ISSN1672-7681
DOIs
Publication statusPublished - 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Keywords

  • IL-6
  • immunosuppression
  • TGFβ
  • tumor microenvironment
  • vaccines

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