TY - JOUR

T1 -  of intact tumor fragments with anti-PD-1 and anti-CTLA-4 influences the expansion and specificity of tumor-infiltrating lymphocytes

AU - Hulen, Thomas Morgan

AU - Friese, Christina

AU - Kristensen, Nikolaj Pagh

AU - Granhøj, Joachim Stoltenborg

AU - Borch, Troels Holz

AU - Peeters, Marlies J.W.

AU - Donia, Marco

AU - Andersen, Mads Hald

AU - Hadrup, Sine Reker

AU - Svane, Inge Marie

AU - Met, Özcan

N1 - Publisher Copyright: Copyright © 2023 Hulen, Friese, Kristensen, Granhøj, Borch, Peeters, Donia, Andersen, Hadrup, Svane and Met.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - adoptive cell immunotherapy

KW - cancer immunotherapy

KW - checkpoint inhibition

KW - DNA Barcoding

KW - metastatic melanoma

KW - tumor microenevironment

KW - tumor-infiltrating lymphocyte (TIL)

U2 - 10.3389/fimmu.2023.1180997

DO - 10.3389/fimmu.2023.1180997

M3 - Journal article

C2 - 37359554

AN - SCOPUS:85162707522

VL - 14

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1180997

ER -