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

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.

SUBMITTER: Lee HJ

PROVIDER: S-EPMC9019109 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Lee Hyo-Jung HJ Song Kwon-Ho KH Oh Se Jin SJ Kim Suyeon S Cho Eunho E Kim Jungwon J Park Yun Gyu YG Lee Kyung-Mi KM Yee Cassian C Song Seung-Hwa SH Chang Suhwan S Choi Jungmin J Jung Sang Taek ST Kim Tae Woo TW

Nature communications 20220419 1

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 o ...[more]

PMID: 35440620

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Project description:Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular-targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo. Metabolomics approach was used to illustrate the global metabolic changes. 13C isotopomer tracing experiment and Seahorse XF analysis were undertaken to determine the activity of fatty acid oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate the prognostic role of CPT1A. Either RNA interference or pharmacological blockade by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by colony formation assay. Mitochondrial membrane potential, apoptosis and neutral lipid content were measured by flow cytometry analysis using JC-1, Annexin V and LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis were detected by western blot. Xenografts were treated with Etomoxir, radiation, or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red O staining respectively. Liquid chromatography coupled with tandem mass spectrometry approach was used to identify CPT1A-binding proteins. The interaction of CPT1A and Rab14 were detected by immunoprecipitation, immunofluorescence and in situ proximity ligation analysis. Fragment docking and direct coupling combined computational protein-protein interaction prediction method were used to predict the binding interface. Fatty acid trafficking was measured by pulse-chase assay using BODIPY C16 and MitoTracker Red probe. Results: FAO was active in radiation-resistant NPC cells, and the rate-limiting enzyme of FAO, carnitine palmitoyl transferase 1 A (CPT1A), was consistently up-regulated in these cells. The protein level of CPT1A was significantly associated with poor overall survival of NPC patients following radiotherapy. Inhibition of CPT1A re-sensitized NPC cells to radiation therapy by activating mitochondrial apoptosis both in vitro and in vivo. In addition, we identified Rab14 as a novel CPT1A binding protein. The CPT1A-Rab14 interaction facilitated fatty acid trafficking from lipid droplets to mitochondria, which decreased radiation-induced lipid accumulation and maximized ATP production. Knockdown of Rab14 attenuated CPT1A-mediated fatty acid trafficking and radiation resistance. Conclusion: An active FAO is a vital signature of NPC radiation resistance. Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects of radiotherapy in NPC patients. Importantly, the CPT1A-Rab14 interaction plays roles in CPT1A-mediated radiation resistance by facilitating fatty acid trafficking. This interaction could be an attractive interface for the discovery of novel CPT1A inhibitors.

Project description:BackgroundPhotothermal therapy (PTT) is a highly effective treatment for solid tumors and can induce long-term immune memory worked like an in situ vaccine. Nevertheless, PTT inevitably encounters photothermal resistance of tumor cells, which hinders therapeutic effect or even leads to tumor recurrence. Naïve CD8+ T cells are mainly metabolized by oxidative phosphorylation (OXPHOS), followed by aerobic glycolysis after activation. And the differentiate of effector CD8+ T cell (CD8+ Teff) into central memory CD8+ T cell (CD8+ TCM) depends on fatty acid oxidation (FAO) to meet their metabolic requirements, which is regulated by adenosine monophosphate activated protein kinase (AMPK). In addition, the tumor microenvironment (TME) is severely immunosuppressive, conferring additional protection against the host immune response mediated by PTT.MethodsMetformin (Met) down-regulates NADH/NADPH, promotes the FAO of CD8+ T cells by activating AMPK, increases the number of CD8+ TCM, which boosts the long-term immune memory of tumor-bearing mice treated with PTT. Here, a kind of PLGA microspheres co-encapsulated hollow gold nanoshells and Met (HAuNS-Met@MS) was constructed to inhibit the tumor progress. 2-Deoxyglucose (2DG), a glycolysis inhibitor for cancer starving therapy, can cause energy loss of tumor cells, reduce the heat stress response of tumor cell, and reverse its photothermal resistance. Moreover, 2DG prevents N-glycosylation of proteins that cause endoplasmic reticulum stress (ERS), further synergistically enhance PTT-induced tumor immunogenic cell death (ICD), and improve the effect of immunotherapy. So 2DG was also introduced and optimized here to solve the metabolic competition among tumor cells and immune cells in the TME.ResultsWe utilized mild PTT effect of HAuNS to propose an in situ vaccine strategy based on the tumor itself. By targeting the metabolism of TME with different administration strategy of 2DG and perdurable action of Met, the thermotolerance of tumor cells was reversed, more CD8+ TCMs were produced and more effective anti-tumor was presented in this study.ConclusionThe Step-by-Step starving-photothermal therapy could not only reverse the tumor thermotolerance, but also enhance the ICD and produce more CD8+ TCM during the treatment.

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

Publications

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

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