NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1

Zhang, Xiaozhen; Huang, Xing; Xu, Jian; Li, Enliang; Lao, Mengyi; Tang, Tianyu; Zhang, Gang; Guo, Chengxiang; Zhang, Xiaoyu; Chen, Wen; Yadav, Dipesh Kumar; Bai, Xueli; Liang, Tingbo

doi:10.1038/s41467-021-24769-3

Cited by 77 publications

(60 citation statements)

References 54 publications

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“…8 24 To address some of these obstacles, recent studies, including our previous published work, have suggested therapy comprizing combinations of immune costimulation-based strategies that could markedly augment the immune treatment effect against PDAC. [25][26][27] In theory, targeting TNFR2 might modulate immunological features and remove the immunosuppressive PDAC TME, thus increasing anti-PD-L1 therapy's antitumor activity. The present study aimed to assess the function and mechanism of TNFR2 in PDAC and the potential of a combination of TNFR2 blockade and PD-L1 blockage to treat pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

Zhang

Lao

et al. 2022

J Immunother Cancer

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BackgroundsIn advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.MethodsTumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry, immunofluorescence, western blotting, and ELISAs. The in vitro mechanism that TNFR2 regulates programmed cell death 1 ligand 1 (PD-L1) was investigated using immunofluorescence, immunohistochemistry, flow cytometry, western blotting, and chromatin immunoprecipitation (ChIP). In vivo efficacy and mechanistic studies, using C57BL/6 mice and nude mice with KPC cell-derived subcutaneous and orthotopic tumors, employed antibodies against TNFR2 and PD-L1. Survival curves were constructed for the orthotopic model and a genetically engineered PDAC model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre). Mass cytometry, immunohistochemistry, and flow cytometry analyzed local and systemic alterations in the immunophenotype.ResultsTNFR2 showed high expression and is a prognostic factor in CD8+ T cell-enriched pancreatic cancer. TNFR2 promotes tumorigenesis and progression of pancreatic cancer via dual effect: suppressing cancer immunogenicity and partially accelerating tumor growth. TNFR2 positivity correlated with PD-L1, and in vitro and in vivo, it could regulate the expression of PDL1 at the transcription level via the p65 NF-κB pathway. Combining anti-TNFR2 and PD-L1 antibodies eradicated tumors, prolonged overall survival in pancreatic cancer, and induced strong antitumor immune memory and secondary prevention by reducing the infiltration of Tregs and tumor-associated macrophages and inducing CD8+ T cell activation in the PDAC microenvironment. Finally, the antitumor immune response derived from combination therapy is mainly dependent on CD8+ T cells, partially dependent on CD4+ T cells, and independent of natural killer cells.ConclusionsAnti-TNFR2 and anti-PD-L1 combination therapy eradicated tumors by inhibiting their growth, relieving tumor immunosuppression, and generating robust memory recall.

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Section: Introductionmentioning

confidence: 99%

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

Zhang

Lao

et al. 2022

J Immunother Cancer

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“…Inhibition of NEK2 thereby sensitizes PD-L1 blockade and synergistically enhances the immune response against pancreatic cancer. Combinatorial inhibition of NEK2 and PD-L1 significantly improves therapeutic efficacy in pancreatic cancer in preclinical models [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma

Schulz

Wetzel

Eichberger

et al. 2021

IJMS

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The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

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“…T cells can gain the ability to eliminate tumor cells by expressing PD-1 ( 41 ). However, tumor cells and APCs can express PD-L1, the ligand of PD-1 ( 42 , 43 ) ( Figure 1 ). By binding to PD-1, TIL apoptosis is induced on the one hand and CD4+ differentiation into regulatory cells (Treg) is stimulated on the other hand ( 44 , 45 ).…”

Section: Dna Damage Repair Is Related To Innate Immunity and Tumor Immune Escapementioning

confidence: 99%

DNA Damage Repair in Brain Tumor Immunotherapy

Zhao

et al. 2022

Front. Immunol.

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With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as “cold tumors” that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

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NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1

Cited by 77 publications

References 54 publications

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma

DNA Damage Repair in Brain Tumor Immunotherapy

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