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Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma
The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well und...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361538/ https://www.ncbi.nlm.nih.gov/pubmed/37484198 http://dx.doi.org/10.1158/2767-9764.CRC-22-0514 |
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author | Lee, Moon Hee Theodoropoulos, Jason Huuhtanen, Jani Bhattacharya, Dipabarna Järvinen, Petrus Tornberg, Sara Nísen, Harry Mirtti, Tuomas Uski, Ilona Kumari, Anita Peltonen, Karita Draghi, Arianna Donia, Marco Kreutzman, Anna Mustjoki, Satu |
author_facet | Lee, Moon Hee Theodoropoulos, Jason Huuhtanen, Jani Bhattacharya, Dipabarna Järvinen, Petrus Tornberg, Sara Nísen, Harry Mirtti, Tuomas Uski, Ilona Kumari, Anita Peltonen, Karita Draghi, Arianna Donia, Marco Kreutzman, Anna Mustjoki, Satu |
author_sort | Lee, Moon Hee |
collection | PubMed |
description | The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well understood. In this study, we analyzed the tumor samples (n = 58) from treatment-naïve patients with renal cell carcinoma (RCC), “pre-rapidly expanded” TILs (pre-REP TIL, n = 15) and “rapidly expanded” TILs (REP TIL, n = 25) according to a clinical-grade TIL production protocol, with single-cell RNA (scRNA)+TCRαβ-seq (TCRαβ sequencing), TCRβ-sequencing (TCRβ-seq), and flow cytometry. REP TILs encompassed a greater abundance of CD4(+) than CD8(+) T cells, with increased LAG-3 and low PD-1 expressions in both CD4(+) and CD8(+) T cell compartments compared with the pre-REP TIL and tumor T cells. The REP protocol preferentially expanded small clones of the CD4(+) phenotype (CD4, IL7R, KLRB1) in the TME, indicating that the largest exhausted T cell clones in the tumor do not expand during the expansion protocol. In addition, by generating a catalog of RCC-associated TCR motifs from >1,000 scRNA+TCRαβ-seq and TCRβ-seq RCC, healthy and other cancer sample cohorts, we quantified the RCC-associated TCRs from the expansion protocol. Unlike the low-remaining amount of anti-viral TCRs throughout the expansion, the quantity of the RCC-associated TCRs was high in the tumors and pre-REP TILs but decreased in the REP TILs. Our results provide an in-depth understanding of the origin, phenotype, and TCR specificity of RCC TIL products, paving the way for a more rationalized production of TILs. SIGNIFICANCE: TILs are a heterogenous group of immune cells that recognize and attack the tumor, thus are utilized in various clinical trials. In our study, we explored the TILs in patients with kidney cancer by expanding the TILs using a clinical-grade protocol, as well as observed their characteristics and ability to recognize the tumor using in-depth experimental and computational tools. |
format | Online Article Text |
id | pubmed-10361538 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-103615382023-07-22 Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma Lee, Moon Hee Theodoropoulos, Jason Huuhtanen, Jani Bhattacharya, Dipabarna Järvinen, Petrus Tornberg, Sara Nísen, Harry Mirtti, Tuomas Uski, Ilona Kumari, Anita Peltonen, Karita Draghi, Arianna Donia, Marco Kreutzman, Anna Mustjoki, Satu Cancer Res Commun Research Article The successful use of expanded tumor-infiltrating lymphocytes (TIL) in adoptive TIL therapies has been reported, but the effects of the TIL expansion, immunophenotype, function, and T cell receptor (TCR) repertoire of the infused products relative to the tumor microenvironment (TME) are not well understood. In this study, we analyzed the tumor samples (n = 58) from treatment-naïve patients with renal cell carcinoma (RCC), “pre-rapidly expanded” TILs (pre-REP TIL, n = 15) and “rapidly expanded” TILs (REP TIL, n = 25) according to a clinical-grade TIL production protocol, with single-cell RNA (scRNA)+TCRαβ-seq (TCRαβ sequencing), TCRβ-sequencing (TCRβ-seq), and flow cytometry. REP TILs encompassed a greater abundance of CD4(+) than CD8(+) T cells, with increased LAG-3 and low PD-1 expressions in both CD4(+) and CD8(+) T cell compartments compared with the pre-REP TIL and tumor T cells. The REP protocol preferentially expanded small clones of the CD4(+) phenotype (CD4, IL7R, KLRB1) in the TME, indicating that the largest exhausted T cell clones in the tumor do not expand during the expansion protocol. In addition, by generating a catalog of RCC-associated TCR motifs from >1,000 scRNA+TCRαβ-seq and TCRβ-seq RCC, healthy and other cancer sample cohorts, we quantified the RCC-associated TCRs from the expansion protocol. Unlike the low-remaining amount of anti-viral TCRs throughout the expansion, the quantity of the RCC-associated TCRs was high in the tumors and pre-REP TILs but decreased in the REP TILs. Our results provide an in-depth understanding of the origin, phenotype, and TCR specificity of RCC TIL products, paving the way for a more rationalized production of TILs. SIGNIFICANCE: TILs are a heterogenous group of immune cells that recognize and attack the tumor, thus are utilized in various clinical trials. In our study, we explored the TILs in patients with kidney cancer by expanding the TILs using a clinical-grade protocol, as well as observed their characteristics and ability to recognize the tumor using in-depth experimental and computational tools. American Association for Cancer Research 2023-07-18 /pmc/articles/PMC10361538/ /pubmed/37484198 http://dx.doi.org/10.1158/2767-9764.CRC-22-0514 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
spellingShingle | Research Article Lee, Moon Hee Theodoropoulos, Jason Huuhtanen, Jani Bhattacharya, Dipabarna Järvinen, Petrus Tornberg, Sara Nísen, Harry Mirtti, Tuomas Uski, Ilona Kumari, Anita Peltonen, Karita Draghi, Arianna Donia, Marco Kreutzman, Anna Mustjoki, Satu Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title | Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title_full | Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title_fullStr | Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title_full_unstemmed | Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title_short | Immunologic Characterization and T cell Receptor Repertoires of Expanded Tumor-infiltrating Lymphocytes in Patients with Renal Cell Carcinoma |
title_sort | immunologic characterization and t cell receptor repertoires of expanded tumor-infiltrating lymphocytes in patients with renal cell carcinoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361538/ https://www.ncbi.nlm.nih.gov/pubmed/37484198 http://dx.doi.org/10.1158/2767-9764.CRC-22-0514 |
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