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

Authors
Lee, Hyo-JungSong, Kwon-HoOh, Se JinKim, SuyeonCho, EunhoKim, JungwonPark, Yun GyuLee, Kyung-MiYee, CassianSong, Seung-HwaChang, SuhwanChoi, JungminJung, Sang TaekKim, Tae Woo
Issue Date
19-4월-2022
Publisher
NATURE PORTFOLIO
Citation
NATURE COMMUNICATIONS, v.13, no.1
Indexed
SCIE
SCOPUS
Journal Title
NATURE COMMUNICATIONS
Volume
13
Number
1
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/141785
DOI
10.1038/s41467-022-29611-y
ISSN
2041-1723
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. Translationally controlled tumor protein (TCTP) regulates several cellular processes, including apoptosis, and is overexpressed in several cancer types. Here, the authors report that high levels of TCTP are associated with poor response to anti-PD-L1 and that TCTP targeting increases the efficacy of T cell-mediated anti-tumor therapy.
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