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IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM

INTRODUCTION: The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could...

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Autores principales: Zannikou, Markella, Duffy, Joseph T, Levine, Rebecca N, Seblani, Maggie, Liu, Qianli, Presser, Aaron, Arrieta, Victor A, Chen, Christopher J, Sonabend, Adam M, Horbinski, Craig M, Lee-Chang, Catalina, Miska, Jason, Lesniak, Maciej S, Gottschalk, Stephen, Balyasnikova, Irina V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923337/
https://www.ncbi.nlm.nih.gov/pubmed/36759014
http://dx.doi.org/10.1136/jitc-2022-006239
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author Zannikou, Markella
Duffy, Joseph T
Levine, Rebecca N
Seblani, Maggie
Liu, Qianli
Presser, Aaron
Arrieta, Victor A
Chen, Christopher J
Sonabend, Adam M
Horbinski, Craig M
Lee-Chang, Catalina
Miska, Jason
Lesniak, Maciej S
Gottschalk, Stephen
Balyasnikova, Irina V
author_facet Zannikou, Markella
Duffy, Joseph T
Levine, Rebecca N
Seblani, Maggie
Liu, Qianli
Presser, Aaron
Arrieta, Victor A
Chen, Christopher J
Sonabend, Adam M
Horbinski, Craig M
Lee-Chang, Catalina
Miska, Jason
Lesniak, Maciej S
Gottschalk, Stephen
Balyasnikova, Irina V
author_sort Zannikou, Markella
collection PubMed
description INTRODUCTION: The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target. METHODS: RNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models. RESULTS: IL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients’ and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells. CONCLUSIONS: We demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.
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spelling pubmed-99233372023-02-14 IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM Zannikou, Markella Duffy, Joseph T Levine, Rebecca N Seblani, Maggie Liu, Qianli Presser, Aaron Arrieta, Victor A Chen, Christopher J Sonabend, Adam M Horbinski, Craig M Lee-Chang, Catalina Miska, Jason Lesniak, Maciej S Gottschalk, Stephen Balyasnikova, Irina V J Immunother Cancer Immune Cell Therapies and Immune Cell Engineering INTRODUCTION: The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target. METHODS: RNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models. RESULTS: IL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients’ and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells. CONCLUSIONS: We demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies. BMJ Publishing Group 2023-02-09 /pmc/articles/PMC9923337/ /pubmed/36759014 http://dx.doi.org/10.1136/jitc-2022-006239 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immune Cell Therapies and Immune Cell Engineering
Zannikou, Markella
Duffy, Joseph T
Levine, Rebecca N
Seblani, Maggie
Liu, Qianli
Presser, Aaron
Arrieta, Victor A
Chen, Christopher J
Sonabend, Adam M
Horbinski, Craig M
Lee-Chang, Catalina
Miska, Jason
Lesniak, Maciej S
Gottschalk, Stephen
Balyasnikova, Irina V
IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title_full IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title_fullStr IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title_full_unstemmed IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title_short IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM
title_sort il15 modification enables car t cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in gbm
topic Immune Cell Therapies and Immune Cell Engineering
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9923337/
https://www.ncbi.nlm.nih.gov/pubmed/36759014
http://dx.doi.org/10.1136/jitc-2022-006239
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