Author
Listed:
- Roberta Zappasodi
(Ludwig Collaborative and Swim Across America Laboratory, MSK
Parker Institute for Cancer Immunotherapy, MSK
Weill Cornell Medicine)
- Inna Serganova
(Weill Cornell Medicine
Department of Neurology, MSK)
- Ivan J. Cohen
(Department of Neurology, MSK
Gerstner Sloan Kettering Graduate School of Biomedical Sciences, MSK)
- Masatomo Maeda
(Department of Neurology, MSK)
- Masahiro Shindo
(Department of Neurology, MSK)
- Yasin Senbabaoglu
(Ludwig Collaborative and Swim Across America Laboratory, MSK
Genentech)
- McLane J. Watson
(University of Pittsburgh)
- Avigdor Leftin
(Department of Medical Physics, MSK)
- Rachana Maniyar
(Ludwig Collaborative and Swim Across America Laboratory, MSK)
- Svena Verma
(Ludwig Collaborative and Swim Across America Laboratory, MSK
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine)
- Matthew Lubin
(Department of Neurology, MSK)
- Myat Ko
(Department of Neurology, MSK)
- Mayuresh M. Mane
(Department of Neurology, MSK)
- Hong Zhong
(Ludwig Collaborative and Swim Across America Laboratory, MSK)
- Cailian Liu
(Ludwig Collaborative and Swim Across America Laboratory, MSK)
- Arnab Ghosh
(Ludwig Collaborative and Swim Across America Laboratory, MSK)
- Mohsen Abu-Akeel
(Ludwig Collaborative and Swim Across America Laboratory, MSK)
- Ellen Ackerstaff
(Department of Medical Physics, MSK)
- Jason A. Koutcher
(Weill Cornell Medicine
Department of Medical Physics, MSK
MSK
MSK)
- Ping-Chih Ho
(University of Lausanne
University of Lausanne)
- Greg M. Delgoffe
(University of Pittsburgh)
- Ronald Blasberg
(Department of Neurology, MSK
MSK)
- Jedd D. Wolchok
(Ludwig Collaborative and Swim Across America Laboratory, MSK
Parker Institute for Cancer Immunotherapy, MSK
Weill Cornell Medicine
MSK)
- Taha Merghoub
(Ludwig Collaborative and Swim Across America Laboratory, MSK
Parker Institute for Cancer Immunotherapy, MSK
Weill Cornell Medicine
MSK)
Abstract
Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells1. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis1. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8+ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (Treg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of Treg cells is dependent on Treg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with Treg cell function in the presence of glucose.
Suggested Citation
Roberta Zappasodi & Inna Serganova & Ivan J. Cohen & Masatomo Maeda & Masahiro Shindo & Yasin Senbabaoglu & McLane J. Watson & Avigdor Leftin & Rachana Maniyar & Svena Verma & Matthew Lubin & Myat Ko , 2021.
"CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours,"
Nature, Nature, vol. 591(7851), pages 652-658, March.
Handle:
RePEc:nat:nature:v:591:y:2021:i:7851:d:10.1038_s41586-021-03326-4
DOI: 10.1038/s41586-021-03326-4
Download full text from publisher
As the access to this document is restricted, you may want to search for a different version of it.
Citations
Citations are extracted by the
CitEc Project, subscribe to its
RSS feed for this item.
Cited by:
- Nils-Petter Rudqvist & Maud Charpentier & Claire Lhuillier & Erik Wennerberg & Sheila Spada & Caroline Sheridan & Xi Kathy Zhou & Tuo Zhang & Silvia C. Formenti & Jennifer S. Sims & Alicia Alonso & Sa, 2023.
"Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors,"
Nature Communications, Nature, vol. 14(1), pages 1-23, December.
- Xinyu Tang & Xinrui Mao & Peiwen Ling & Muxin Yu & Hua Pan & Jiaming Wang & Mingduo Liu & Hong Pan & Wen Qiu & Nan Che & Kai Zhang & Feifan Bao & Hongwei Peng & Qiang Ding & Shui Wang & Wenbin Zhou, 2024.
"Glycolysis inhibition induces anti-tumor central memory CD8+T cell differentiation upon combination with microwave ablation therapy,"
Nature Communications, Nature, vol. 15(1), pages 1-20, December.
- Xijiao Ren & Zhuo Cheng & Jinming He & Xuemei Yao & Yingqi Liu & Kaiyong Cai & Menghuan Li & Yan Hu & Zhong Luo, 2023.
"Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer,"
Nature Communications, Nature, vol. 14(1), pages 1-22, December.
Corrections
All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:591:y:2021:i:7851:d:10.1038_s41586-021-03326-4. See general information about how to correct material in RePEc.
If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.
We have no bibliographic references for this item. You can help adding them by using this form .
If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.
For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .
Please note that corrections may take a couple of weeks to filter through
the various RePEc services.