TY - JOUR
T1 - The antitumor activity of TGFβ-specific T cells is dependent on IL-6 signaling
AU - Perez-Penco, Maria
AU - Byrdal, Mikkel
AU - Lara de la Torre, Lucia
AU - Ballester, Marta
AU - Khan, Shawez
AU - Siersbæk, Majken
AU - Lecoq, Inés
AU - Madsen, Cecilie Oelvang
AU - Kjeldsen, Julie Westerlin
AU - Svane, Inge Marie
AU - Hansen, Morten
AU - Donia, Marco
AU - Johansen, Julia Sidenius
AU - Olsen, Lars Rønn
AU - Grøntved, Lars
AU - Chen, Inna Markovna
AU - Arnes, Luis
AU - Holmström, Morten Orebo
AU - Andersen, Mads Hald
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - IL-6
KW - immunosuppression
KW - TGFβ
KW - tumor microenvironment
KW - vaccines
U2 - 10.1038/s41423-024-01238-7
DO - 10.1038/s41423-024-01238-7
M3 - Journal article
C2 - 39653766
AN - SCOPUS:85211901553
VL - 22
SP - 111
EP - 126
JO - Cellular & Molecular Immunology
JF - Cellular & Molecular Immunology
SN - 1672-7681
IS - 1
M1 - 104659
ER -