Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy
Abstract Introduction Adoptive cellular therapy with tumor‐infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the “prone‐to‐exhaustion” phenotype of TIL and poor persistence in vivo. This calls...
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.5095 |
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| author | Hao Feng Ling Qiu Zixiao Shi Yao Sheng Peipei Zhao Di Zhou Fei Li Hailin Yu Yanan You Hui Wang Ming Li Shurong Zhu Yan Du Jun Cui Jingwei Sun Yarong Liu Hua Jiang Xin Wu |
| author_facet | Hao Feng Ling Qiu Zixiao Shi Yao Sheng Peipei Zhao Di Zhou Fei Li Hailin Yu Yanan You Hui Wang Ming Li Shurong Zhu Yan Du Jun Cui Jingwei Sun Yarong Liu Hua Jiang Xin Wu |
| author_sort | Hao Feng |
| collection | DOAJ |
| description | Abstract Introduction Adoptive cellular therapy with tumor‐infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the “prone‐to‐exhaustion” phenotype of TIL and poor persistence in vivo. This calls for a robust expansion process to produce a large number of cells for clinical usage while at the same time maintaining favorable anti‐tumor function and memory phenotype. Previous studies showed that the PI3K‐AKT signaling pathway plays a key role in the regulation of T cell activation, differentiation and memory formation. Method We modulated the PI3K‐AKT pathway in TIL isolated from cervical and ovarian cancer by application of AKT or PI3K inhibitors or CRISPR knockout of AKT1 and/or AKT2, and characterized their effects on TIL phenotype and effector function. Mechanistic study was further performed with RNA‐seq analysis of AKT1/2 KO TIL in comparison to control TIL. Result The inhibition of either PI3K or AKT led to an increase in the population of effector CD8+ T cells with upregulation of activation markers, elevated CD39−CD69− memory T cells, and significantly enhanced cytotoxicity when cocultured with tumor cell lines and patient‐derived tumor samples. Moreover, dual knockout of AKT1 and AKT2 largely phenocopies the functional impact of AKT or PI3K inhibition on TIL. This result was further validated by RNA‐seq analysis indicating that AKT1/2 ablation primarily regulates T cell differentiation and function‐related programs. Conclusion Modulation of PI3K‐AKT signaling represents a promising strategy to enhance TIL stemness and cytotoxicity and improve the clinical outcome of current TIL‐based therapy to treat solid tumors. |
| format | Article |
| id | doaj-art-99fa77ab873e42639618fa69468134cb |
| institution | OA Journals |
| issn | 2045-7634 |
| language | English |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-99fa77ab873e42639618fa69468134cb2025-08-20T01:53:22ZengWileyCancer Medicine2045-76342023-02-011233313332710.1002/cam4.5095Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapyHao Feng0Ling Qiu1Zixiao Shi2Yao Sheng3Peipei Zhao4Di Zhou5Fei Li6Hailin Yu7Yanan You8Hui Wang9Ming Li10Shurong Zhu11Yan Du12Jun Cui13Jingwei Sun14Yarong Liu15Hua Jiang16Xin Wu17Department of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaGrit Biotechnology Co., Ltd. Shanghai Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaDepartment of Gynecology Obstetrics and Gynecology Hospital of Fudan University Shanghai People's Republic of ChinaAbstract Introduction Adoptive cellular therapy with tumor‐infiltrating lymphocytes (TIL) has demonstrated promising clinical benefits in several solid tumors, but the efficacy of this therapy might be compromised by the “prone‐to‐exhaustion” phenotype of TIL and poor persistence in vivo. This calls for a robust expansion process to produce a large number of cells for clinical usage while at the same time maintaining favorable anti‐tumor function and memory phenotype. Previous studies showed that the PI3K‐AKT signaling pathway plays a key role in the regulation of T cell activation, differentiation and memory formation. Method We modulated the PI3K‐AKT pathway in TIL isolated from cervical and ovarian cancer by application of AKT or PI3K inhibitors or CRISPR knockout of AKT1 and/or AKT2, and characterized their effects on TIL phenotype and effector function. Mechanistic study was further performed with RNA‐seq analysis of AKT1/2 KO TIL in comparison to control TIL. Result The inhibition of either PI3K or AKT led to an increase in the population of effector CD8+ T cells with upregulation of activation markers, elevated CD39−CD69− memory T cells, and significantly enhanced cytotoxicity when cocultured with tumor cell lines and patient‐derived tumor samples. Moreover, dual knockout of AKT1 and AKT2 largely phenocopies the functional impact of AKT or PI3K inhibition on TIL. This result was further validated by RNA‐seq analysis indicating that AKT1/2 ablation primarily regulates T cell differentiation and function‐related programs. Conclusion Modulation of PI3K‐AKT signaling represents a promising strategy to enhance TIL stemness and cytotoxicity and improve the clinical outcome of current TIL‐based therapy to treat solid tumors.https://doi.org/10.1002/cam4.5095AKT inhibitorAKT KOPI3K inhibitorTIL manufacturetumor‐infiltrating lymphocyte therapy |
| spellingShingle | Hao Feng Ling Qiu Zixiao Shi Yao Sheng Peipei Zhao Di Zhou Fei Li Hailin Yu Yanan You Hui Wang Ming Li Shurong Zhu Yan Du Jun Cui Jingwei Sun Yarong Liu Hua Jiang Xin Wu Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy Cancer Medicine AKT inhibitor AKT KO PI3K inhibitor TIL manufacture tumor‐infiltrating lymphocyte therapy |
| title | Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy |
| title_full | Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy |
| title_fullStr | Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy |
| title_full_unstemmed | Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy |
| title_short | Modulation of intracellular kinase signaling to improve TIL stemness and function for adoptive cell therapy |
| title_sort | modulation of intracellular kinase signaling to improve til stemness and function for adoptive cell therapy |
| topic | AKT inhibitor AKT KO PI3K inhibitor TIL manufacture tumor‐infiltrating lymphocyte therapy |
| url | https://doi.org/10.1002/cam4.5095 |
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