Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy

Ayala‐Mar, Sergio; Donoso‐Quezada, Javier; González‐Valdez, José

doi:10.1155/2021/8839978

Cited by 36 publications

(25 citation statements)

References 111 publications

(183 reference statements)

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“…Accordingly, the patient selection based on non-tissue PD-L1 assessments seems not ready for clinical utilization and requires technology improvements [ 104 ]. Exosomal PD-L1 in metastatic gastric cancer has been discovered to be an independent predictor for OS and was negatively correlated with CD4+ or CD8+ T-cell count and granzyme B levels [ 105 , 106 ]. Ishiba et al examined the possibility of detecting ctRNA in the blood of 760 patients with solid tumors, including 44 cases of gastric cancer.…”

Section: The Role Of Liquid Biopsy In Disease Monitoringmentioning

confidence: 99%

The Emerging Role of Liquid Biopsy in Gastric Cancer

Lengyel

Hussain

Trapani

et al. 2021

JCM

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(1) Background: Liquid biopsy (LB) is a novel diagnostic method with the potential of revolutionizing the prevention, diagnosis, and treatment of several solid tumors. The present paper aims to summarize the current knowledge and explore future possibilities of LB in the management of metastatic gastric cancer. (2) Methods: This narrative review examined the most recent literature on the use of LB-based techniques in metastatic gastric cancer and the current LB-related clinical trial landscape. (3) Results: In gastric cancer, the detection of circulating cancer cells (CTCs) has been recognized to have a prognostic role in all the disease stages. In the setting of localized disease, cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) qualitative and quantitative detection have the potential to inform on the risk of cancer recurrence and metastatic dissemination. In addition, gastric cancer-released exosomes may play an essential part in metastasis formation. In the metastatic setting, the levels of cfDNA show a positive correlation with tumor burden. There is evidence that circulating tumor microemboli (CTM) in the blood of metastatic patients is an independent prognostic factor for shorter overall survival. Gastric cancer-derived exosomal microRNAs or clonal mutations and copy number variations detectable in ctDNA may contribute resistance to chemotherapy or targeted therapies, respectively. There is conflicting and limited data on CTC-based PD-L1 verification and cfDNA-based Epstein–Barr virus detection to predict or monitor immunotherapy responses. (4) Conclusions: Although preliminary studies analyzing LBs in patients with advanced gastric cancer appear promising, more research is required to obtain better insights into the molecular mechanisms underlying resistance to systemic therapies. Moreover, validation and standardization of LB methods are crucial before introducing them in clinical practice. The feasibility of repeatable, minimally invasive sampling opens up the possibility of selecting or dynamically changing therapies based on prognostic risk or predictive biomarkers, such as resistance markers. Research is warranted to exploit a possible transforming area of cancer care.

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Section: The Role Of Liquid Biopsy In Disease Monitoringmentioning

confidence: 99%

The Emerging Role of Liquid Biopsy in Gastric Cancer

Lengyel

Hussain

Trapani

et al. 2021

JCM

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“…It has been proved that exosomal PD-L1 suppresses T cell activation and function [24]. In our study, we examined whether LEX PD-L1si could reverse T-cell tolerance and immunosuppression, and restore anti-tumor immunity.…”

Section: Lex Pd-l1si Promotes T-cell Activation and Antigen-specific Ctl Responsementioning

confidence: 96%

“…Second, high levels of immunosuppressive factors in TEXs mediate immune tolerance [22,23]. Among these immunosuppressive factors, programmed cell death proteinligand 1 (PD-L1), one of immune checkpoint molecules that interacts with programmed cell death protein-1 (PD-1), is expressed on the surface of the tumor cells and on TEXs [24,22]. Exosomal PD-L1, which is resistant to anti-PD-L1 therapy, can transmit immunosuppressive signals to T cells and anti-apoptotic signals to tumor cells, inducing local and systemic immunosuppression and promotion of tumor growth [22].…”

Section: Introductionmentioning

confidence: 99%

Enhancing the anti-leukemia immunity of leukemia-derived exosome-based vaccine by downregulation of PD-L1 expression

Huang¹,

Z²,

Zhang³

et al. 2021

Preprint

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Cell-released nanovesicles can induce anti-leukemia immunity. Leukemia cell-derived exosomes (LEXs) are promising anti-tumor vaccine components for cancer immunotherapy. Nonetheless, LEX-based vaccines show modest potency in vivo, likely due to the presence of immunosuppressive PD-L1 proteins in the exosomes. We hypothesized that targeting exosomal PD-L1 could optimize LEX-based vaccines. To test this hypothesis, we compared the capacity of exosomes derived from PD-L1-silenced leukemia cells (LEXPD-L1si) and non-modified exosomes to induce anti-leukemia immunity.Lentivirus-mediated PD-L1 shRNA was used to downregulate PD-L1 expression in parental leukemia cells and LEXs. LEXPD-L1si were characterized by electron microscopy, western blotting, and flow cytometry, and their anti-leukemia immune effects were tested on immune cells and in animal models.In the present study, lentivirus-mediated PD-L1 shRNA successfully downregulated PD-L1 expression in parental leukemia cells and in LEXs. LEXPD-L1si induced better DC maturation and subsequently enhanced T-cell activation, as compared with non-modified LEXs. Consistently, immunization with LEXPD-L1si induced greater T-cell proliferation and Th1 cytokine release. LEXPD-L1si was a more potent inducer of antigen-specific cytotoxic lymphocyte (CTL) response. Finally, we vaccinated DBA/2 mice with exosome formulations to test their ability to induce both protective and therapeutic anti-tumor CTL responses in vivo. Vaccination with LEXPD-L1si strongly inhibited tumor growth and prolonged survival. Downregulation of exosomal PD-L1 expression in LEXs effectively induce more potent anti-leukemia immunity. Therefore our strategy for optimizing LEX-based vaccine has a potential application in leukemia immunotherapy.

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“…PD-L1 is expressed both at the surface of exosomes and within them. However, the mechanisms that control PD-L1 distribution among the different cellular compartments are not well understood [63,90]. ESCRT-accessory proteins seem to be involved in determining the cellular distribution of PD-L1.…”

Section: Exosomes and Pd-l1mentioning

confidence: 99%

Tumor-Derived Exosomes: Hidden Players in PD-1/PD-L1 Resistance

Vautrot

Bentayeb

Causse

et al. 2021

Cancers

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Recently, immunotherapy has garnered increasing importance in cancer therapy, leading to substantial improvements in patient care and survival. By blocking the immune checkpoints—protein regulators of the immune system—immunotherapy prevents immune tolerance toward tumors and reactivates the immune system, prompting it to fight cancer cell growth and diffusion. A widespread strategy for this is the blockade of the interaction between PD-L1 and PD-1. However, while patients generally respond well to immunotherapy, a certain proportion of patients present tumors that resist these treatments. This portion can be very high in some cancers and hinders cancer curability. For this reason, current efforts are focusing on combining PD-1/PD-L1 immunotherapy with the targeting of other immune checkpoints to counter resistance and achieve better results. Exosomes, small vesicles secreted by almost any cell, including tumor cells, have proven to be key actors in this resistance. The exosomes released by tumor cells spread the immune-suppressive properties of the tumor throughout the tumor microenvironment and participate in establishing metastatic niches. In this review, we will describe immune checkpoints and immune modulators whose presence in tumor-derived exosomes (TEXs) has been established. We will focus on the most promising proteins under scrutiny for use in combination with PD-1 blockade therapy in a clinical setting, such as PD-L1, CTLA-4, TIM-3, CD73/39, LAG-3, and TIGIT. We will explore the immunosuppressive impact of these exosomal proteins on a variety of immune cells. Finally, we will discuss how they can change the game in immunotherapy and guide therapeutic decisions, as well as the current limits of this approach. Depending on the viewpoint, these exosomal proteins may either provide key missing information on tumor growth and resistance mechanisms or they may be the next big challenge to overcome in improving cancer treatment.

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Clinical Implications of Exosomal PD-L1 in Cancer Immunotherapy

Cited by 36 publications

References 111 publications

The Emerging Role of Liquid Biopsy in Gastric Cancer

The Emerging Role of Liquid Biopsy in Gastric Cancer

Enhancing the anti-leukemia immunity of leukemia-derived exosome-based vaccine by downregulation of PD-L1 expression

Tumor-Derived Exosomes: Hidden Players in PD-1/PD-L1 Resistance

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