Anti-metabolite chemotherapy increases LAG-3 expressing tumor-infiltrating lymphocytes which can be targeted by combination immune checkpoint blockade.

Autor:	Principe N; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Phung AL; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia., Stevens KLP; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia., Elaskalani O; Telethon Kids Institute, Nedlands, Western Australia, Australia., Wylie B; Telethon Kids Institute, Nedlands, Western Australia, Australia., Tilsed CM; Perelman School of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Sheikh F; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Orozco Morales ML; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; Telethon Kids Institute, Nedlands, Western Australia, Australia., Kidman J; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Marcq E; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerpen, Belgium.; Brussels Center for Immunology, Vrije Universiteit Brussel, Brussels, Belgium.; Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research, Brussels, Belgium., Fisher SA; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia., Nowak AK; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia.; Medical School, The University of Western Australia, Crawley, Western Australia, Australia., McDonnell AM; Telethon Kids Institute, Nedlands, Western Australia, Australia., Lesterhuis WJ; Telethon Kids Institute, Nedlands, Western Australia, Australia., Chee J; Institute for Respiratory Health, National Centre for Asbestos Related Diseases, The University of Western Australia, Perth, Western Australia, Australia jonathan.chee@uwa.edu.au.; School of Biomedical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Sep 28; Vol. 12 (9). Date of Electronic Publication: 2024 Sep 28.
DOI:	10.1136/jitc-2023-008568
Abstrakt:	Background: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein/ligand 1 (PD-1/PD-L1) are approved for treatment of multiple cancer types. Chemotherapy is often administered with immune checkpoint blockade (ICB) therapies that target CTLA-4 and/or PD-(L)1. ICB targeting other immune checkpoints such as lymphocyte activating gene-3 (LAG-3) has the potential to improve antitumor responses when combined with chemotherapy. Response to anti-PD-1 ICB is dependent on progenitor exhausted CD8 + T cells (T PEX ) in the tumor, but it is unclear how chemotherapy alters T PEX proportions and phenotype. Methods: Here we investigated whether sequential chemotherapy altered T PEX frequency and immune checkpoint expression in multiple murine tumor models. Results: Two doses of two different anti-metabolite chemotherapies increased tumor infiltrating CD4 + , and CD8 + T PEX expressing LAG-3 in multiple mouse models, which was not restricted to tumor antigen specific CD8 + T cells. To determine if LAG-3 + tumor infiltrating lymphocytes (TILs) could be targeted to improve tumor control, we administered anti-LAG-3 and anti-PD-1 ICB after two doses of chemotherapy and found combination therapy generated robust antitumor responses compared with each agent alone. Both anti-LAG-3 and anti-PD-1 ICB with chemotherapy were required for the complete tumor regression observed. Conclusions: Changes in immune checkpoint expression on TILs during chemotherapy administration informs selection of ICB therapies to combine with. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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