Ectopic CXCR2 expression cells improve the anti-tumor efficiency of CAR-T cells and remodel the immune microenvironment of pancreatic ductal adenocarcinoma

Author(s): Zhengjie Dai ¹ ^, ² ^, ³ ^, ⁴ , Xuan Lin ¹ ^, ² ^, ³ ^, ⁴ , Xu Wang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, , Xuan Zou ¹ ^, ² ^, ³ ^, ⁴ , Yu Yan ¹ ^, ² ^, ³ ^, ⁴ , Ruijie Wang ¹ ^, ² ^, ³ ^, ⁴ , Yusheng Chen ¹ ^, ² ^, ³ ^, ⁴ , Yesiboli Tasiheng ¹ ^, ² ^, ³ ^, ⁴ , Mingjian Ma ¹ ^, ² ^, ³ ^, ⁴ , Xu Wang ¹ ^, ² ^, ³ ^, ⁴ , He Cheng ¹ ^, ² ^, ³ ^, ⁴ ^, , Xianjun Yu ¹ ^, ² ^, ³ ^, ⁴ ^, , Chen Liu ¹ ^, ² ^, ³ ^, ⁴ ^,

Publication date (Electronic): 2 March 2024

Journal: Cancer Immunology, Immunotherapy

Publisher: Springer Berlin Heidelberg

Keywords: CXCR2, Cell therapy, Pancreatic ductal adenocarcinoma, Tumor microenvironment

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Abstract

Background

Recent progressions in CAR-T cell therapy against pancreatic ductal adenocarcinoma (PDAC) remain disappointing, which are partially attributed to the immunosuppressive microenvironment including macrophage-mediated T cell repletion.

Methods

We first characterized the expression patterns of macrophage-relevant chemokines and identified CXCR2 as the key factor regulating T cell trafficking and tumor-specific accumulation in PDAC microenvironment. After that, we synthesized and introduced a CXCR2 expression cascade into Claudin18.2 CAR-T cells and compared the behaviors of CAR-T cells in vitro and in vivo. The therapeutic potential of CXCR2 CAR-T was evaluated in two different allogeneic models: subcutaneous allografts and metastatic PDAC models.

Results

The results showed that CXCR2 CAR-T not only reduced the size of allografted PDAC tumors, but also completely eliminated the formation of metastases. Lastly, we investigated the tumor tissues and found that expression of ectopic CXCR2 significantly improved tumor-targeted infiltration and residence of T cells and reduced the presence of MDSCs and CXCR2 + macrophages in PDAC microenvironment.

Conclusion

Our studies suggested that ectopic CXCR2 played a significant and promising role in improving the efficiency of CAR-T therapy against primary and metastatic PDAC and partially reversed the immune-suppressive microenvironment.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03648-y.

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Is Open Access

CAR-T cell therapy: current limitations and potential strategies

Robert C. Sterner, Rosalie M. Sterner (2021)

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

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Author and article information

Contributors

Xu Wang: wangxu2013@fudan.edu.cn

He Cheng: chenghe@fudanpci.org

Xianjun Yu: yuxianjun@fudanpci.org

Chen Liu: liuchen@fudanpci.org

Journal

Journal ID (nlm-ta): Cancer Immunol Immunother

Journal ID (iso-abbrev): Cancer Immunol Immunother

Title: Cancer Immunology, Immunotherapy

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-7004

ISSN (Electronic): 1432-0851

Publication date (Electronic): 2 March 2024

Publication date PMC-release: 2 March 2024

Publication date (Print): 2024

Volume: 73

Issue: 4

Electronic Location Identifier: 61

Affiliations

[1 ]Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, ( https://ror.org/00my25942) No. 270 Dong An Road, Xu-Hui District, Shanghai, 200032 China

[2 ]GRID grid.8547.e, ISNI 0000 0001 0125 2443, Department of Oncology, Shanghai Medical College, , Fudan University, ; Shanghai, 200032 China

[3 ]GRID grid.452404.3, ISNI 0000 0004 1808 0942, Shanghai Pancreatic Cancer Institute, ; Shanghai, 200032 China

[4 ]Pancreatic Cancer Institute, Fudan University, ( https://ror.org/013q1eq08) Shanghai, 200032 China

[5 ]Cancer Research Institute, Shanghai Key Laboratory of Radiation Oncology, , Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China

Article

Publisher ID: 3648

DOI: 10.1007/s00262-024-03648-y

PMC ID: 10908625

PubMed ID: 38430267

SO-VID: d32d65bf-2e1a-4efd-8420-02c0bbb9caaa

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 8 December 2023

Date accepted : 29 January 2024