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Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes.

Authors :
Hulen, Thomas Morgan
Friese, Christina
Kristensen, Nikolaj Pagh
Granhøj, Joachim Stoltenborg
Borch, Troels Holz
Peeters, Marlies J. W.
Donia, Marco
Andersen, Mads Hald
Hadrup, Sine Reker
Svane, Inge Marie
Met, Özcan
Source :
Frontiers in Immunology; 2024, p1-15, 15p
Publication Year :
2024

Abstract

Checkpoint inhibition (CPI) therapy and adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL-based ACT) are the two most effective immunotherapies for the treatment of metastatic melanoma. While CPI has been the dominating therapy in the past decade, TIL-based ACT is beneficial for individuals even after progression on previous immunotherapies. Given that notable differences in response have been made when used as a subsequent treatment, we investigated how the qualities of TILs changed when the ex vivo microenvironment of intact tumor fragments were modulated with checkpoint inhibitors targeting programmed death receptor 1 (PD-1) and cytotoxic Tlymphocyte-associated protein 4 (CTLA-4). Initially, we show that unmodified TILs from CPI-resistant individuals can be produced, are overwhelmingly terminally differentiated, and are capable of responding to tumor. We then investigate these properties in ex vivo checkpoint modulated TILs finding that that they retain these qualities. Lastly, we confirmed the specificity of the TILs to the highest responding tumor antigens, and identified this reactivity resides largely in CD39+CD69+ terminally differentiated populations. Overall, we found that anti-PD-1 will alter the proliferative capacity while anti-CTLA4 will influence breadth of antigen specificity. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
16643224
Database :
Complementary Index
Journal :
Frontiers in Immunology
Publication Type :
Academic Journal
Accession number :
178755996
Full Text :
https://doi.org/10.3389/fimmu.2023.1180997