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Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

ABSTRACT: Various predictive biomarkers are needed to select candidates for optimal and individualized treatments. Tumor-infiltrating immune cells have gained increasing interest in cancer research for the prediction of therapeutic response and survival. However, the role of dendritic cells (DCs) in PD-1 blockade immunotherapy remains unclear. In this study, we identified a population of PD-1+ DCs in the tumor microenvironment (TME) of cervical cancer (CC). The accumulation of PD-1+ DCs in cervical tumors was correlated with advanced stages, elevated preoperative squamous cell carcinoma antigen levels and lymph-vascular space invasion. PD-1 expression was induced on activated tumor-associated DCs (TADCs) in vitro compared with their resting counterparts. This PD-1+ DC population was characterized by reduced secretion of cytokines (IL-12, TNF-α, and IL-1β) and dysfunctional induction of T cell proliferation and cytotoxic reaction. PD-1 blockade significantly reinvigorated PD-1+ DCs to release IL-12, TNF-α, and IL-1β compared with PD-1- DCs. TILs from samples with higher PD-1+ DC infiltration could be induced to achieve a greater killing effect of PD-1 blockade treatment. Our findings suggested a role for PD-1+ DCs in immune surveillance dysfunction and CC progression. PD-1+ DC density in the TME may serve as a diagnostic factor for predicting the optimal beneficiaries of PD-1/PD-L1 blockade immunotherapy in CC.

SUBMITTER: Wang YM

PROVIDER: S-EPMC8837238 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

Wang Yu-Meng YM Qiu Jun-Jun JJ Qu Xin-Yu XY Peng Jing J Lu Chong C Zhang Meng M Zhang Ming-Xing MX Qi Xing-Ling XL Lv Bin B Guo Jing-Jing JJ Guo Chen-Yan CY Li Gui-Ling GL Hua Ke-Qin KQ

Oncoimmunology 20220209 1

Various predictive biomarkers are needed to select candidates for optimal and individualized treatments. Tumor-infiltrating immune cells have gained increasing interest in cancer research for the prediction of therapeutic response and survival. However, the role of dendritic cells (DCs) in PD-1 blockade immunotherapy remains unclear. In this study, we identified a population of PD-1+ DCs in the tumor microenvironment (TME) of cervical cancer (CC). The accumulation of PD-1+ DCs in cervical tumors ...[more]

PMID: 35154907

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Project description:BackgroundDysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy.MethodsKaplan-Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune "hot" and "cold" pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Two in vivo models bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy.ResultsMET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune "hot" and "cold" pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer.ConclusionsThis study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.

Dataset Information

Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

Publications

Accumulation of dysfunctional tumor-infiltrating PD-1+ DCs links PD-1/PD-L1 blockade immunotherapeutic response in cervical cancer.

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