Reshaping the Tumor Immune Microenvironment to Improve CAR-T Cell-based Cancer Immunotherapy

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2024 Aug 26

PMID 39187850

Authors

Xueting Xia

Zongxin Yang

Qisi Lu

Zhenyun Liu

Lei Wang

Jinwen Du

Yuhua Li

Dong-Hua Yang

Shaojie Wu

Affiliations

Soon will be listed here.

Abstract

In many hematologic malignancies, the adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated notable success; nevertheless, further improvements are necessary to optimize treatment efficacy. Current CAR-T therapies are particularly discouraging for solid tumor treatment. The immunosuppressive microenvironment of tumors affects CAR-T cells, limiting the treatment's effectiveness and safety. Therefore, enhancing CAR-T cell infiltration capacity and resolving the immunosuppressive responses within the tumor microenvironment could boost the anti-tumor effect. Specific strategies include structurally altering CAR-T cells combined with targeted therapy, radiotherapy, or chemotherapy. Overall, monitoring the tumor microenvironment and the status of CAR-T cells is beneficial in further investigating the viability of such strategies and advancing CAR-T cell therapy.

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References

Martinez M, Moon E . CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment. Front Immunol. 2019; 10:128. PMC: 6370640. DOI: 10.3389/fimmu.2019.00128. View

Meister H, Look T, Roth P, Pascolo S, Sahin U, Lee S . Multifunctional mRNA-Based CAR T Cells Display Promising Antitumor Activity Against Glioblastoma. Clin Cancer Res. 2022; 28(21):4747-4756. DOI: 10.1158/1078-0432.CCR-21-4384. View

Sharma P, Hu-Lieskovan S, Wargo J, Ribas A . Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017; 168(4):707-723. PMC: 5391692. DOI: 10.1016/j.cell.2017.01.017. View

Yang F, Zhang F, Ji F, Chen J, Li J, Chen Z . Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors. Front Immunol. 2023; 14:1175920. PMC: 10287952. DOI: 10.3389/fimmu.2023.1175920. View

Zhao K, Ren C, Tang D, Zhao L, Chen X, Wang Y . The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice. Front Immunol. 2023; 14:1101769. PMC: 9905118. DOI: 10.3389/fimmu.2023.1101769. View

Altvater B, Kailayangiri S, Perez Lanuza L, Urban K, Greune L, Flugge M . HLA-G and HLA-E Immune Checkpoints Are Widely Expressed in Ewing Sarcoma but Have Limited Functional Impact on the Effector Functions of Antigen-Specific CAR T Cells. Cancers (Basel). 2021; 13(12). PMC: 8227123. DOI: 10.3390/cancers13122857. View

Saleh K, Cheminant M, Chiron D, Burroni B, Ribrag V, Sarkozy C . Tumor Microenvironment and Immunotherapy-Based Approaches in Mantle Cell Lymphoma. Cancers (Basel). 2022; 14(13). PMC: 9265015. DOI: 10.3390/cancers14133229. View

Mehra V, Agliardi G, Dias Alves Pinto J, Shafat M, Garai A, Green L . AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival. J Immunother Cancer. 2023; 11(9). PMC: 10503365. DOI: 10.1136/jitc-2023-007002. View

Sun R, Luo H, Su J, Di S, Zhou M, Shi B . Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice. Mol Ther. 2020; 29(1):60-74. PMC: 7791086. DOI: 10.1016/j.ymthe.2020.09.034. View

10.

Alizadeh D, Wong R, Gholamin S, Maker M, Aftabizadeh M, Yang X . IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. Cancer Discov. 2021; 11(9):2248-2265. PMC: 8561746. DOI: 10.1158/2159-8290.CD-20-1661. View

11.

Zhong F, Lin Y, Zhao L, Yang C, Ye Y, Shen Z . Reshaping the tumour immune microenvironment in solid tumours via tumour cell and immune cell DNA methylation: from mechanisms to therapeutics. Br J Cancer. 2023; 129(1):24-37. PMC: 10307880. DOI: 10.1038/s41416-023-02292-0. View

12.

Song Q, Shang J, Zhang C, Chen J, Zhang L, Wu X . Transcription factor RUNX3 promotes CD8 T cell recruitment by CCL3 and CCL20 in lung adenocarcinoma immune microenvironment. J Cell Biochem. 2020; 121(5-6):3208-3220. DOI: 10.1002/jcb.29587. View

13.

Pang N, Shi J, Qin L, Chen A, Tang Y, Yang H . IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. J Hematol Oncol. 2021; 14(1):118. PMC: 8323212. DOI: 10.1186/s13045-021-01128-9. View

14.

Tian Y, Wen C, Zhang Z, Liu Y, Li F, Zhao Q . CXCL9-modified CAR T cells improve immune cell infiltration and antitumor efficacy. Cancer Immunol Immunother. 2022; 71(11):2663-2675. PMC: 10991162. DOI: 10.1007/s00262-022-03193-6. View

15.

Doering T, Crawford A, Angelosanto J, Paley M, Ziegler C, Wherry E . Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity. 2012; 37(6):1130-44. PMC: 3749234. DOI: 10.1016/j.immuni.2012.08.021. View

16.

Goldberg L, Haas E, Urak R, Vyas V, Pathak K, Garcia-Mansfield K . Immunometabolic Adaptation of CD19-Targeted CAR T Cells in the Central Nervous System Microenvironment of Patients Promotes Memory Development. Cancer Res. 2024; 84(7):1048-1064. PMC: 10984768. DOI: 10.1158/0008-5472.CAN-23-2299. View

17.

Prinz L, Riet T, Neureuther D, Lennartz S, Chrobok D, Hubbe H . An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL. Cell Rep Med. 2024; 5(2):101421. PMC: 10897622. DOI: 10.1016/j.xcrm.2024.101421. View

18.

Luo Y, Chen Z, Sun M, Li B, Pan F, Ma A . IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy. Biomaterials. 2022; 281:121341. DOI: 10.1016/j.biomaterials.2021.121341. View

19.

Yamaguchi Y, Gibson J, Ou K, Lopez L, Ng R, Leggett N . PD-L1 blockade restores CAR T cell activity through IFN-γ-regulation of CD163+ M2 macrophages. J Immunother Cancer. 2022; 10(6). PMC: 9226933. DOI: 10.1136/jitc-2021-004400. View

20.

Mascaux C, Angelova M, Vasaturo A, Beane J, Hijazi K, Anthoine G . Immune evasion before tumour invasion in early lung squamous carcinogenesis. Nature. 2019; 571(7766):570-575. DOI: 10.1038/s41586-019-1330-0. View