Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade

Pang, Kun; Wei, Liuya; Yang, Dong; Ma, Yuechao; Wang, Wei; Wang, Guangyue; Cao, Mengxi; Dong, Jiajun; Chen, Yu-Ang; Zhang, Peng; Lin, Hui; Xu, Hao; Pan, Deng; Chen, Zhe‐Sheng; Han, Conghui

doi:10.1016/j.drup.2022.100907

Cited by 69 publications

(28 citation statements)

References 162 publications

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“…Upon CD155 binding to TIGIT, the ITT-like motif is phosphorylated and binds to Grb2, bringing about the recruitment of SH domain-containing inositol-5-phosphatase (SHIP1) and impeding multiple signaling pathways [28]. SHIP1 is a crucial inhibitor of the phosphatidylinositol 3-kinase (PI3K) signaling, as it hydrolyzes PI (3,4,5)P3, thereby inhibiting kinases containing pleckstrin homology (PH) structural domains, such as Akt, Btk, and phospholipase C-γ [34]. Moreover, premature binding of TIGIT to CD155 hinders phosphorylation of Erk and MEK kinases, which are initiators of the MAPK signaling cascade.…”

Section: Direct Inhibitory Effects Of Tigit In T and Nk Cellsmentioning

confidence: 99%

“…For instance, only 20.06% of lung cancer patients are expected to benefit from ICIs, with less than 1.5% of patients experiencing complete responses and around 15% showing partial responses [3]. This is partly due to the complex interplay between cancer cells and the immune system [4][5][6]. For example, some cancer cells can downregulate molecules that promote T-cell activation, leading to resistance to ICIs [7,8].…”

Section: Introductionmentioning

confidence: 99%

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Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.

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Section: Direct Inhibitory Effects Of Tigit In T and Nk Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

et al. 2023

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“…34 However, the clinical efficacy of PD-1/PD-L1 blockade is limited by low response rate and resistance mechanisms. 35 Therefore, identifying new immune checkpoint targets or combination strategies to enhance the outcome and response rate of tumor immunotherapy is a current research focus and challenge. VISTA may be a potential candidate, as it exhibits distinct expression patterns and mechanisms of action from the PD-1/PD-L1 pathway, and has demonstrated potent antitumor effects in vitro and in vivo experiments, especially when combined with PD-1/PD-L1 inhibitors.…”

Section: ■ Discussion and Conclusionmentioning

confidence: 99%

“…Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have emerged as one of the most successful antitumor therapies, demonstrating the efficacy of immune checkpoint inhibitors as antitumor drug targets . However, the clinical efficacy of PD-1/PD-L1 blockade is limited by low response rate and resistance mechanisms . Therefore, identifying new immune checkpoint targets or combination strategies to enhance the outcome and response rate of tumor immunotherapy is a current research focus and challenge.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Sun,

He,

Wang

et al. 2024

J. Med. Chem.

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VISTA (V-domain Ig suppressor of T cell activation) is a novel immune checkpoint protein and represents a promising target for cancer immunotherapy. Here, we report the design, synthesis, and evaluation of a series of methoxy-pyrimidinebased VISTA small molecule inhibitors with potent antitumor activity. By employing molecular docking and microscale thermophoresis (MST) assay, we identified a lead compound A1 that binds to VISTA protein with high affinity and optimized its structure. A4 was then obtained, which exhibited the strongest binding ability to VISTA protein, with a K D value of 0.49 ± 0.20 μM. In vitro, A4 significantly activated peripheral blood mononuclear cells (PBMCs) induced the release of cytokines such as IFN-γ and enhanced the cytotoxicity of PBMCs against tumor cells. In vivo, A4 displayed potent antitumor activity and synergized with PD-L1 antibody to enhance the therapeutic effect against cancer. These results suggest that compound A4 is an effective VISTA small molecule inhibitor, providing a basis for the future development of VISTA-targeted drugs.

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“…With the ongoing development of precision medicine, immunotherapeutic drugs, particularly immune checkpoint inhibitors (ICIs), have made breakthroughs in cancer treatment. Inhibitors of the programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) play an important therapeutic role in a wide range of tumors (6)(7)(8)(9). In the phase 3 TOPAZ-1 trial in 685 patients with advanced BTC, durvalumab (a PD-L1 inhibitor) in combination with gemcitabine and cisplatin improved OS compared to placebo plus chemotherapy (median OS: 12.8 months vs 11.5 months, P=0.021) (10).…”

Section: Introductionmentioning

confidence: 99%

Immune-related adverse events correlate with the efficacy of PD-1 inhibitors combination therapy in advanced cholangiocarcinoma patients: A retrospective cohort study

Zhang

Wang

et al. 2023

Front. Immunol.

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BackgroundWhether irAEs can predict the efficacy of PD-1 inhibitors in cholangiocarcinoma (CCA) has not been assessed. Therefore, this study aims to investigate the correlation between irAEs and the therapeutic effect of PD-1 inhibitors combination therapy in patients with advanced CCA.MethodsAll patients with CCA who were consecutively admitted to the inpatient unit of our hospital and received PD-1 inhibitors combination therapy between September 2020 and April 2022 were screened. In total, 106 patients with CCA were screened out. We then followed up these patients until October 2022. Due to perioperative use (n=28), less than 2 cycles of PD-1 inhibitor therapy (n=9), incomplete data (n=8) and no pathological report (n=2), 59 patients were included in the final analysis. The patients were divided into the irAEs cohort and the non-irAEs cohort according to whether they experienced irAEs or not. The Log-Rank test was performed to compare the difference in survival time between these two cohorts. We then applied multivariate COX regression analysis to investigate whether irAEs were independent prognostic factors for survival in patients with advanced CCA.ResultsFinally, 32 patients were included in the irAEs cohort and 27 patients in the non-irAEs cohort. A total of 32 patients (54.2%) had any-grade irAEs, of which 4 patients (6.8%) had grade 3-4 irAEs. The most common irAEs were thyroid toxicity (30.5%) and dermatologic toxicity (30.5%). There were no notable differences in demographics and clinical characteristics between the irAEs and non-irAEs cohorts, except for total bilirubin level (P=0.026) and relapse (P=0.016). The disease control rate (DCR) in the irAEs cohort was higher than in the non-irAEs cohort (90.6% vs 70.4%, P=0.047). Median overall survival (OS) and median progression-free survival (PFS) were better in the irAEs cohort than in the non-irAEs cohort (OS: 21.2 vs 10.0 months, P<0.001; PFS: 9.0 vs 4.4 months, P=0.003). Multivariate COX regression analysis showed that irAEs were independent prognostic factors for OS and PFS (OS: HR=0.133, 95% CI: 0.039-0.452, P=0.001; PFS: HR=0.435, 95% CI: 0.202-0.934, P=0.033).ConclusionIrAEs correlated with improved DCR, OS, and PFS in advanced CCA patients receiving PD-1 inhibitors combination therapy.

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Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade

Cited by 69 publications

References 162 publications

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

Immune-related adverse events correlate with the efficacy of PD-1 inhibitors combination therapy in advanced cholangiocarcinoma patients: A retrospective cohort study

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