Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges

Li, Zhitao; Sun, Guoqiang; Cheng, Yufeng; Wu, Liangliang; Wang, Qian; Lv, Chengyu; Zhou, Yichan; Xia, Yongxiang; Tang, Weiwei

doi:10.3389/fonc.2021.771335

Cited by 23 publications

(24 citation statements)

References 207 publications

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“…Thus, PD1/PD-L1 expression can be impacted by regulating many of the aforementioned regulators to improve the response to PD1/PD-L1 inhibitors in patients with or without tumors. In our study, we demonstrated that PD-L1 was significantly declined in unresponsive tumors compared with those that were positive in anti-PD1 responses in HCC patients, which is consistent with a previous study ( 7 ). Additionally, to analyze which genes caused primary drug resistance to anti-PD1 treatment, we sequenced 289 nanostring panel RNA and found increased GUSB expression in the anti-PD1 resistance group, thus finding new predictive molecules and therapeutic targets for anti-PD1 therapy in HCC.…”

Section: Discussionsupporting

confidence: 93%

“…In the tumor microenvironment, tumor cells and antigen-presenting cells (APCs) upregulate PD-L1 expression to evade immune surveillance through adaptive and internal immune tolerance. Furthermore, the increase in PD-L1 is also a prerequisite for the effectiveness of anti-PD1/PD-L1 monoclonal antibodies ( 7 ). In murine experiments, Juneja et al.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, initial drug resistance exists before exposure, preventing the drug from blocking tumor progression ( 6 ). PD1/PD-L1 resistance is associated with loss of initial and costimulatory signals, the expression level of PD1/PD-L1 on the cell surface, tumor microenvironment, and epigenetic inheritance ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

et al. 2022

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Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

et al. 2022

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“…However, tumor cells can exploit this mechanism to escape the immune system by upregulating the expression of suppressive molecules that interact with T cells, rendering them incapable of killing [ 27 ]. For example, the binding of PD-L1 expressed by tumor cells to PD-1 on the surface of TILs weakens the immune role of T cells, which causes tumor immune escape and promotes tumor progression [ 40 ]. To date, more than ten types of ICs have been discovered, such as PD-1, PD-L1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain containing-3 (TIM-3), and lymphocyte-activation gene 3 (LAG3/CD223), of which the most extensively studied are CTLA-4 and PD-1/PD-L1.…”

Section: Immune Evasion and Icismentioning

confidence: 99%

Impact of Diets on Response to Immune Checkpoint Inhibitors (ICIs) Therapy against Tumors

Zhang

et al. 2022

Life

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Immunotherapy has revolutionized the established therapeutics against tumors. As the major immunotherapy approach, immune checkpoint inhibitors (ICIs) achieved remarkable success in the treatment of malignancies. However, the clinical gains are far from universal and durable, because of the primary and secondary resistance of tumors to the therapy, or side effects induced by ICIs. There is an urgent need to find safe combinatorial strategies that enhance the response of ICIs for tumor treatment. Diets have an excellent safety profile and have been shown to play pleiotropic roles in tumor prevention, growth, invasion, and metastasis. Accumulating evidence suggests that dietary regimens bolster not only the tolerability but also the efficacy of tumor immunotherapy. In this review, we discussed the mechanisms by which tumor cells evade immune surveillance, focusing on describing the intrinsic and extrinsic mechanisms of resistance to ICIs. We also summarized the impacts of different diets and/or nutrients on the response to ICIs therapy. Combinatory treatments of ICIs therapy with optimized diet regimens own great potential to enhance the efficacy and durable response of ICIs against tumors, which should be routinely considered in clinical settings.

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“…Through the JAK and STAT signaling pathways, CXCL10-CXCR3 is hypothesized to regulate PD-L1 synthesis in fibroblasts ( 17 ). Activation of PD-L1/PD-1 poses great difficulties for cancer therapy ( 18 ), which is often associated with cytotoxic T lymphocyte malfunction. In patients with gynecologic malignancies, elevated PD-L1 expression may be a useful biomarker for predicting clinical outcomes ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Tumor Microenvironment Regulating Factor That Facilitates Tumor Immune Infiltration in Cervical Cancer

Huang

Wang

et al. 2022

Front. Oncol.

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Cervical cancer is one of the most common gynecologic malignancies and one of the leading causes of cancer-related deaths in women worldwide. There are more than 30 categories of human papillomavirus infections in the genital tract. The recently discovered immune checkpoint suppression is a potential approach to improve clinical outcomes in these patients by altering immune cell function. However, many questions remain unanswered in terms of this method. For example, the proportion of responders is limited and the exact mechanism of action is uncertain. The tumor microenvironment (TME) has long been regarded as having nonnegligible influence on effectiveness of immunotherapy. The programmed cell death protein 1 (PD-1) pathway has received much attention due to its involvement in activating T-cell immune checkpoint responses. Since tumor cells may evade immune detection and become highly resistant to conventional treatments, anti-PD-1/PD-L1 antibodies are preferred as a kind of cancer treatment and many have just been licensed. To provide a theoretical basis for the development of new therapies, investigating the effect of tumor microenvironment on the prognosis of cervical cancer is necessary. In this work, immunological scores obtained from the ESTIMATE algorithm were used to differentiate between patients with high and low immune cell infiltration. We identified 11 immunologically significant differentially expressed genes (DEGs). For example, CXCR3 was found to be an important factor in CD8+ T cell recruitment and tumor immunological infiltration in cervical cancer. These results may lead to novel directions of understanding complex interactions between cancer cells and the tumor microenvironment, as well as new treatment options for cervical cancer.

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Various Uses of PD1/PD-L1 Inhibitor in Oncology: Opportunities and Challenges

Cited by 23 publications

References 207 publications

Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma

Impact of Diets on Response to Immune Checkpoint Inhibitors (ICIs) Therapy against Tumors

Identification of Novel Tumor Microenvironment Regulating Factor That Facilitates Tumor Immune Infiltration in Cervical Cancer

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