Targeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes

Hyo-Jung Lee, Kwon-Ho Song, Se Jin Oh, Suyeon Kim, Eunho Cho, Jungwon Kim, Yun gyu Park, Kyung-Mi Lee, Cassian Yee, Seung-Hwa Song, Suhwan Chang, Jungmin Choi, Sang Taek Jung and Tae Woo Kim ()
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Hyo-Jung Lee: Korea university College of Medicine
Kwon-Ho Song: Catholic University of Daegu School of Medicine
Se Jin Oh: Korea university College of Medicine
Suyeon Kim: Korea university College of Medicine
Eunho Cho: Korea university College of Medicine
Jungwon Kim: Korea university College of Medicine
Yun gyu Park: Korea university College of Medicine
Kyung-Mi Lee: Korea university College of Medicine
Cassian Yee: U.T. MD Anderson Cancer Center
Seung-Hwa Song: Korea university College of Medicine
Suhwan Chang: Asan Medical Center
Jungmin Choi: Korea university College of Medicine
Sang Taek Jung: Korea university College of Medicine
Tae Woo Kim: Korea university College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Immunotherapy has emerged as a powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical application. Therefore, identifying immune-resistant factors, which can be targeted by clinically available drugs and it also can be a companion diagnostic marker, is needed to develop combination strategies. Here, using the transcriptome data of patients, and immune-refractory tumor models, we identify TCTP as an immune-resistance factor that correlates with clinical outcome of anti-PD-L1 therapy and confers immune-refractory phenotypes, decreased T cell trafficking to the tumor and resistance to cytotoxic T lymphocyte-mediated tumor cell killing. Mechanistically, TCTP activates the EGFR-AKT-MCL-1/CXCL10 pathway by phosphorylation-dependent interaction with Na, K ATPase. Furthermore, treatment with dihydroartenimsinin, the most effective agent impending the TCTP-mediated-refractoriness, synergizes with T cell-mediated therapy to control immune-refractory tumors. Thus, our findings suggest a role of TCTP in promoting immune-refractoriness, thereby encouraging a rationale for combination therapies to enhance the efficacy of T cell-mediated therapy.

Date: 2022
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DOI: 10.1038/s41467-022-29611-y

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