1. Ex vivo modulation of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes.
- Author
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Hulen TM, Friese C, Kristensen NP, Granhøj JS, Borch TH, Peeters MJW, Donia M, Andersen MH, Hadrup SR, Svane IM, and Met Ö
- Subjects
- Humans, Immunotherapy, Tumor Microenvironment, Lymphocytes, Tumor-Infiltrating, Melanoma
- 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 T-lymphocyte-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., Competing Interests: IMS has lectured for or had advisory board relationships with MSD, Sanofi Aventis, BMS, Pierre Fabre, Novartis, TILT Biotherapeutics, IO Biotech, and Novo Nordisk. IS has received research grants from Lytix biopharma, IO Biotech, BMS, Adaptimmune, and TILT Biotherapeutics. IS is a co-founder and shareholder for the company IO Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor NO declared a shared parent affiliation with the authors TH, CF, JG, TB, MP, MD, MA, IMS and OM at the time of review., (Copyright © 2023 Hulen, Friese, Kristensen, Granhøj, Borch, Peeters, Donia, Andersen, Hadrup, Svane and Met.)- Published
- 2023
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