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

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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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          Most cited references30

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          Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.

          Cancer incidence and deaths in the United States were projected for the most common cancer types for the years 2020 and 2030 based on changing demographics and the average annual percentage changes in incidence and death rates. Breast, prostate, and lung cancers will remain the top cancer diagnoses throughout this time, but thyroid cancer will replace colorectal cancer as the fourth leading cancer diagnosis by 2030, and melanoma and uterine cancer will become the fifth and sixth most common cancers, respectively. Lung cancer is projected to remain the top cancer killer throughout this time period. However, pancreas and liver cancers are projected to surpass breast, prostate, and colorectal cancers to become the second and third leading causes of cancer-related death by 2030, respectively. Advances in screening, prevention, and treatment can change cancer incidence and/or death rates, but it will require a concerted effort by the research and healthcare communities now to effect a substantial change for the future. ©2014 American Association for Cancer Research.
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            Pancreatic cancer

            Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.
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              Is Open Access

              CAR-T cell therapy: current limitations and potential strategies

              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
                wangxu2013@fudan.edu.cn
                chenghe@fudanpci.org
                yuxianjun@fudanpci.org
                liuchen@fudanpci.org
                Journal
                Cancer Immunol Immunother
                Cancer Immunol Immunother
                Cancer Immunology, Immunotherapy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-7004
                1432-0851
                2 March 2024
                2 March 2024
                2024
                : 73
                : 4
                : 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
                3648
                10.1007/s00262-024-03648-y
                10908625
                38430267
                d32d65bf-2e1a-4efd-8420-02c0bbb9caaa
                © The Author(s) 2024

                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
                : 8 December 2023
                : 29 January 2024
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 82072693, 81902417, 82172884, U21A20374
                Award ID: 82072693, 81902417, 82172884, U21A20374
                Award Recipient :
                Funded by: the Scientific Innovation Project of Shanghai Education Committee
                Award ID: 2019-01-07-00-07-E00057
                Award ID: 2019-01-07-00-07-E00057
                Award Recipient :
                Funded by: Shanghai Municipal Science and Technology Major Project
                Award ID: 21JC1401500
                Award ID: 21JC1401500
                Award Recipient :
                Funded by: Clinical and Scientific Innovation Project of Shanghai Hospital Development Center
                Award ID: SHDC12018109
                Award ID: SHDC12018109
                Award Recipient :
                Funded by: Clinical Research Plan of Shanghai Hospital Development Center
                Award ID: SHDC2020CR1006A
                Award ID: SHDC2020CR1006A
                Award Recipient :
                Funded by: National Key Research and Development Program of China
                Award ID: 2020YFA0803202
                Award ID: 2020YFA0803202
                Award Recipient :
                Funded by: Xuhui District Artificial Intelligence Medical Hospital Cooperation Project
                Award ID: 2021-011
                Award ID: 2021-011
                Award Recipient :
                Categories
                Research
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2024

                Oncology & Radiotherapy
                cxcr2,cell therapy,pancreatic ductal adenocarcinoma,tumor microenvironment

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