Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9
Open Access
- 19 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-14
- https://doi.org/10.1038/s41467-020-19672-2
Abstract
CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers.Funding Information
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (R01 CA200539, R01 CA211073, R01 CA214811, R01 CA239255)
- Cancer Prevention and Research Institute of Texas (RR180044)
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute
This publication has 45 references indexed in Scilit:
- p38 MAPK in Myeloma Cells Regulates Osteoclast and Osteoblast Activity and Induces Bone DestructionCancer Research, 2012
- Th9 cells promote antitumor immune responses in vivoJCI Insight, 2012
- Robust tumor immunity to melanoma mediated by interleukin-9–producing T cellsNature Medicine, 2012
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- Pronounced Hypoxia in Models of Murine and Human Leukemia: High Efficacy of Hypoxia-Activated Prodrug PR-104PLOS ONE, 2011
- Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody ReceptorClinical Cancer Research, 2011
- Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19Blood, 2010
- Roles of Idiotype-Specific T Cells in Myeloma Cell Growth and Survival: Th1 and CTL Cells Are Tumoricidal while Th2 Cells Promote Tumor GrowthCancer Research, 2008
- Idiotype‐specific T lymphocytes in monoclonal gammopathies: evidence for the presence of CD4+ and CD8+ subsetsBritish Journal of Haematology, 1997
- Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2Cell, 1993