EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

Peng, Shunli; Wang, Rong; Zhang, Xiaojuan; Ma, Yuyan; Zhong, Longhui; Li, Ké; Nishiyama, Akihiro; Arai, Sachiko; Yano, Seiji; Wang, Wei

doi:10.1186/s12943-019-1073-4

Cited by 178 publications

(154 citation statements)

References 51 publications

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“…Using the ProcartaPlexHuman Cytokine/Chemokine/Growth Factor Panel and the ProcartaPlexHuman Immuno-Oncology Checkpoint Panel, we found that patients with lower baseline plasma HGF or IL-8 levels, or a decrease of plasma IL-8, or an increase of plasma TIM-3 or CD152 level at 8 weeks after treatment may bene t more from camrelizumab with apatinib. Recent studies showed that high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts, which was associated with poor responses to checkpoint blockade therapies (17)(18)(19)(20). IL-8 is secreted by malignant tumor and stroma cells across many different types of tumor, and is a member of the CXC chemokine family identi ed as a chemotactic factor for neutrophils (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

Liu

et al. 2020

Preprint

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Background: We recently reported the results of a phase II clinical trial that the combinational use of camrelizumab plus apatinib induced an objective response rate (ORR) at 43.3% in advanced triple-negative breast cancer (TNBC) patients. This study presents the analysis of potential tumor and blood biomarkers for the patients responded to the combinational therapy. Methods: Stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells and the protein expression of programmed death protein 1 (PD-1) and PD-L1 were evaluated in tumor samples collected before and after the treatment. Peripheral blood samples were collected before treatment, 2-weeks and 8-weeks after treatment. 59 cytokines/chemokines, growth factors, or checkpoint-related proteins, blood immune cell subpopulations were analyzed in the blood samples. The correlation between biomarkers and clinical outcomes including ORR, progression-free survival (PFS), and overall survival (OS) was analyzed. Results: Upon database lock, the ORR of 28 evaluable patients was 46.4%. An increase of tumor-infiltrating CD8+ T cells more than 15% during therapy was significantly associated with higher ORR (P=0.040). Patients with lower baseline plasma levels of HGF or IL-8 were more likely to respond to the combinational treatment (P=0.005 or 0.001, respectively), and showed a longer PFS and OS (HGF: PPFS<0.0001, POS<0.0001; IL-8: PPFS<0.0001, POS=0.009). Patients with a decrease of IL-8, or an increase of TIM-3 or CD152 during treatment responded more to the treatment (P=0.008, 0.040, or 0.014, respectively). Responders had a higher baseline CD4+ T cells and B cell proportions in blood than non-responders (P=0.002 and 0.030 respectively). Moreover, patients with higher baseline CD4+ T cells or B cells proportions in blood showed a longer PFS (P<0.001) or a longer OS (P=0.030) respectively. Conclusion: Higher baseline TILs or a greater increase of tumor-infiltrating CD8+ T cells during therapy, lower baseline plasma HGF/IL-8, a decrease of plasma IL-8, an increase of plasma TIM-3/CD152 during therapy, higher baseline CD4+ T cells or B cells proportion in blood are potential biomarkers for the combinational anti-angiogenesis and immunotherapy in advanced TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

Liu

et al. 2020

Preprint

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“…Thus, acquired EGFR‐TKIs resistance promotes the immune escape of lung cancer by upregulating the expression of PD‐L1. PI3K/AKT, MAPK, NF‐Kappa B signaling pathway, and AP‐1 participate in the upregulation of PD‐L1 induced by different EGFR‐TKI resistance mechanisms 154 . Other studies have also confirmed that EGFR/ALK mutations in NSCLC models upregulate PD‐L1 expression by activating the PI3K‐AKT, MEK (Mitogen‐activated protein kinase kinase)/ERK(Extracellular signal‐regulated kinase) pathway 155 .…”

Section: Abnormal Signaling Pathway Transduction and Related Protein mentioning

confidence: 95%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

105

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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“…Reverse transcription, quantitative real-time PCR and Western blotting were performed as described previously (31). Oligonucleotide primers used for SDPR and GAPDH (internal control) were as follows: SDPR: 5'-CTCCGACGCAACCATTT-3'(sense); 5'-CTTTCTTGAGGCTATCCACTT-3' (antisense); GAPDH:5'-AGAAGGTGGGGCTCATTTG-3' (sense); 5'-AGGGGCCATCCACAGTCTTC-3' (antisense); GAPDH: 5'-AGAAGGTGGGGCTCATTTG-3' (sense); 5'-AGGGGCCATCCACAGTCTTC-3' (antisense) (32). All the reactions were performed in triplicate for each sample.…”

Section: Reverse Transcription Quantitative Real-time Pcr and Westermentioning

confidence: 99%

Prognostic Values, ceRNA Network, and Immune Regulation Function of SDPR in KRAS-mutant Lung Cancer

Luo

Peng

Ding

et al. 2020

Preprint

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Background: SDPR plays an important role in formation of pulmonary alveoli. However, the function and values of SDPR remain unknown in lung cancer. We explored prognostic values, expression pattern and biological function of SDPR in NSCLC and KRAS-mutant lung cancers.Methods: SDPR expression were evaluated by RT-qPCR, IHC, Western blotting based on human NSCLC cells, lung adenocarcinoma tissues array, KRAS-mutant transgenetic mice, TCGA and GEO datasets. The prognosis values of SDPR were evaluated by Kaplan–Meier and Cox regression analysis. The bioinformatics implication of SDPR including SDPR-combinated TFs and microRNAs were predicted. In addition, correlations between SDPR, immune checkpoint molecules and tumor infiltration models were illustrated.Results: SDPR expression was downregulated among tumor cells and tissues. Low SDPR expression was an independent factor that correlated with shorter overall survival of patients in both lung cancer and KRAS-mutant subgroup. Meanwhile, ceRNA network to clarify the regulatory and biological functions of SDPR was constructed. Negative correlations were found between SDPR and immune checkpiont moluculars (PD-L1, TNFRSF18, TNFRSF9, and TDO2). Moreover, diversity immune infiltration models were observed in NSCLC with different SDPR expression and copy number variation (CNV) patterns.Conclusions: This study elucidates regulation network of SDPR in KRAS-mutant NSCLC, and illustrates correlations between low SDPR expression and suppressed immune systems, unfolding a prognostic factor and potential target for the treatment of lung cancer, especially for KRAS-mutant NSCLC.

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EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

Cited by 178 publications

References 51 publications

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Prognostic Values, ceRNA Network, and Immune Regulation Function of SDPR in KRAS-mutant Lung Cancer

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