Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy. / Mortensen, Rasmus Erik Johansson; Holmström, Morten Orebo; Lisle, Thomas Landkildehus; Hasselby, Jane P.; Willemoe, Gro L.; Met, Özcan; Marie Svane, Inge; Johansen, Julia; Nielsen, Dorte L.; Chen, Inna M.; Andersen, Mads Hald.

In: Journal for ImmunoTherapy of Cancer, Vol. 11, No. 3, 2023.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Mortensen, REJ, Holmström, MO, Lisle, TL, Hasselby, JP, Willemoe, GL, Met, Ö, Marie Svane, I, Johansen, J, Nielsen, DL, Chen, IM & Andersen, MH 2023, 'Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy', Journal for ImmunoTherapy of Cancer, vol. 11, no. 3. https://doi.org/10.1136/jitc-2022-006432

APA

Mortensen, R. E. J., Holmström, M. O., Lisle, T. L., Hasselby, J. P., Willemoe, G. L., Met, Ö., Marie Svane, I., Johansen, J., Nielsen, D. L., Chen, I. M., & Andersen, M. H. (2023). Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy. Journal for ImmunoTherapy of Cancer, 11(3). https://doi.org/10.1136/jitc-2022-006432

Vancouver

Mortensen REJ, Holmström MO, Lisle TL, Hasselby JP, Willemoe GL, Met Ö et al. Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy. Journal for ImmunoTherapy of Cancer. 2023;11(3). https://doi.org/10.1136/jitc-2022-006432

Author

Mortensen, Rasmus Erik Johansson ; Holmström, Morten Orebo ; Lisle, Thomas Landkildehus ; Hasselby, Jane P. ; Willemoe, Gro L. ; Met, Özcan ; Marie Svane, Inge ; Johansen, Julia ; Nielsen, Dorte L. ; Chen, Inna M. ; Andersen, Mads Hald. / Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy. In: Journal for ImmunoTherapy of Cancer. 2023 ; Vol. 11, No. 3.

Bibtex

@article{d49acd1db41b4fc4ad273ca7796ec662,
title = "Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy",
abstract = "BACKGROUND: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC). METHODS: Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry. RESULTS: PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15. CONCLUSION: A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.",
keywords = "Antigens, Immunotherapy, T-Lymphocytes, Tumor Microenvironment, Vaccination",
author = "Mortensen, {Rasmus Erik Johansson} and Holmstr{\"o}m, {Morten Orebo} and Lisle, {Thomas Landkildehus} and Hasselby, {Jane P.} and Willemoe, {Gro L.} and {\"O}zcan Met and {Marie Svane}, Inge and Julia Johansen and Nielsen, {Dorte L.} and Chen, {Inna M.} and Andersen, {Mads Hald}",
note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2023",
doi = "10.1136/jitc-2022-006432",
language = "English",
volume = "11",
journal = "Journal for ImmunoTherapy of Cancer",
issn = "2051-1426",
publisher = "BioMed Central Ltd.",
number = "3",

}

RIS

TY - JOUR

T1 - Pre-existing TGF-β-specific T-cell immunity in patients with pancreatic cancer predicts survival after checkpoint inhibitors combined with radiotherapy

AU - Mortensen, Rasmus Erik Johansson

AU - Holmström, Morten Orebo

AU - Lisle, Thomas Landkildehus

AU - Hasselby, Jane P.

AU - Willemoe, Gro L.

AU - Met, Özcan

AU - Marie Svane, Inge

AU - Johansen, Julia

AU - Nielsen, Dorte L.

AU - Chen, Inna M.

AU - Andersen, Mads Hald

N1 - Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023

Y1 - 2023

N2 - BACKGROUND: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC). METHODS: Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry. RESULTS: PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15. CONCLUSION: A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.

AB - BACKGROUND: Circulating transforming growth factor-β (TGF-β)-specific T cells that recognize TGF-β-expressing immune regulatory cells have been described in patients with cancer. TGF-β-derived peptide vaccination modulates the tumor microenvironment and has shown clinical effects in animal models of pancreatic cancer (PC). TGF-β-expressing regulatory cells are especially elevated in PC and may prevent the clinical response to immune checkpoint inhibitors (ICIs). Thus, in the present study we investigated the significance of TGF-β-specific T-cell immunity in patients with PC treated with ICI combined with radiotherapy in a randomized phase 2 study (CheckPAC). METHODS: Immune responses to a TGF-β-derived epitope entitled TGF-β-15 as well as epitopes from Clostridium tetani (tetanus) and influenza were measured in peripheral blood mononuclear cells (PBMCs) with interferon-ɣ enzyme-linked immunospot assays. PBMCs were isolated before and after treatment. Correlations between immune response data and clinical data were evaluated with parametric and non-parametric statistical methods. Survival was analyzed with univariate and multivariate Cox-regression. TGF-β-15 specific T cells were isolated and expanded and examined for recognition of autologous regulatory immune cells by flow cytometry. RESULTS: PBMCs from 32 patients were analyzed for immune responses to the TGF-β-derived epitope entitled TGF-β-15. Patients with a strong TGF-β-specific immune response at treatment initiation had longer progression-free and overall survival, compared with patients with a weak or no TGF-β-specific immune response. This remained significant in multivariate analysis. Patients with weak and strong TGF-β-specific responses displayed similar responses towards viral antigens. Furthermore, we show that TGF-β-specific T cells from a clinical responder specifically reacted to and lysed autologous, regulatory immune cells. Finally, mimicking a TGF-β-15 vaccination, we showed that repeated stimulations with the TGF-β-15 epitope in vitro enhanced the immune response to TGF-β-15. CONCLUSION: A strong TGF-β-15 specific immune response was associated with clinical benefit and improved survival after ICI/radiotherapy for patients with PC. Importantly, the lack of TGF-β-specific T cells in some patients was not caused by a general immune dysfunction. TGF-β-specific T cells recognized regulatory immune cells and could be introduced in vitro in patients without spontaneous responses. Taken together, our data suggest that combining TGF-β-based vaccination with ICI/radiotherapy will be beneficial for patients with PC.

KW - Antigens

KW - Immunotherapy

KW - T-Lymphocytes

KW - Tumor Microenvironment

KW - Vaccination

U2 - 10.1136/jitc-2022-006432

DO - 10.1136/jitc-2022-006432

M3 - Journal article

C2 - 36948507

AN - SCOPUS:85150769724

VL - 11

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

SN - 2051-1426

IS - 3

ER -

ID: 341346437