Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases

The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.

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Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

Cancers ◽

10.3390/cancers12123504 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3504

Author(s):

Silvia Pesce ◽

Sara Trabanelli ◽

Clara Di Vito ◽

Marco Greppi ◽

Valentina Obino ◽

...

Keyword(s):

Immune System ◽

Immune Checkpoint ◽

Nk Cell ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Lymphoid Cells ◽

Immune Checkpoints ◽

Tissue Damages ◽

Innate Lymphocytes

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies.

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The Role of Immunotherapy in the Treatment of Advanced Cervical Cancer: Current Status and Future Perspectives

Journal of Clinical Medicine ◽

10.3390/jcm10194523 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4523

Author(s):

Robert Walsh ◽

David Tan

Keyword(s):

Cervical Cancer ◽

Immune Checkpoint ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Current Status ◽

Viral Etiology ◽

Resistance Strategies ◽

Attractive Option

Cervical cancer remains one of the most common cancers in women around the world however therapeutic options in the advanced and recurrent setting are limited. Immune checkpoint inhibitors (ICI) have been considered an attractive option given the viral etiology of cervical cancer although the majority of patients do not benefit from their use. This review summarises current knowledge and use of immune checkpoint blockade in cervical cancer as well as discussing the challenges faced in their clinical application, namely, the role of biomarker-driven ICI use, potential mechanisms of resistance, strategies to overcome such resistance and additional immunotherapy options beyond ICI.

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Overview of Current Progress in Immune Checkpoint Inhibitor Therapy for Advanced Hepatocellular Carcinoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033820947486 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094748

Author(s):

Xinlun Dai ◽

Shupeng Wang ◽

Chunyuan Niu ◽

Bai Ji ◽

Yahui Liu

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Immune Checkpoint ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

Inhibitory Signaling

Hepatocellular carcinoma (HCC) remains to a common cause of tumor mortality worldwide and represents the most common type of lethal hepatic malignancy. The incidence of HCC is swiftly increasing in western countries and southeast Asia. Despite poor prognosis, traditional treatments for advanced HCC appear to be minimally effective or even useless since patients are usually diagnosed in the advanced stage of disease. In recent years, immune checkpoint blockade has shown promising results in multiple pre-clinical and clinical trials of different solid tumors, including advanced HCC. Novel drugs targeting immune checkpoints, such as nivolumab (anti-PD-1), durvalumab (anti-PD-L1), and tremelimumab (anti-CTLA-4) have been shown to be highly effective and relatively safe in monotherapy or in combination treatment of advanced liver cancer. Unlike other immunotherapies, this approach can rouse human anti-tumor immunity by relieving T-cell exhaustion and inhibiting the evasion of HCC by blocking co-inhibitory signaling transduction accurately. In this review, we will provide current knowledge of several major immune checkpoints and summarize recent data from clinical trials that applied immune checkpoint inhibitors alone or in combination. In addition, this review will discuss the limitations and future prospective of immune checkpoint-targeted therapy for advanced HCC.

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Rethinking immune checkpoint blockade: ‘Beyond the T cell’

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001460 ◽

2021 ◽

Vol 9 (1) ◽

pp. e001460 ◽

Cited By ~ 1

Author(s):

Xiuting Liu ◽

Graham D Hogg ◽

David G DeNardo

Keyword(s):

Immune System ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Antitumor Immunity ◽

Checkpoint Inhibitors ◽

Clinical Success ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

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Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Vaccines ◽

10.3390/vaccines8040735 ◽

2020 ◽

Vol 8 (4) ◽

pp. 735

Author(s):

Simran Venkatraman ◽

Jarek Meller ◽

Suradej Hongeng ◽

Rutaiwan Tohtong ◽

Somchai Chutipongtanate

Keyword(s):

Immune Checkpoint ◽

Cancer Genomics ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Immune Checkpoint Blockade ◽

Immune Checkpoints ◽

Master Regulators ◽

New Class ◽

Public Datasets ◽

Molecular Expression

The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40–60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as “master regulators”, have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

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Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice

Cancers ◽

10.3390/cancers11111689 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1689 ◽

Cited By ~ 10

Author(s):

Edoardo Giannini ◽

Andrea Aglitti ◽

Mauro Borzio ◽

Martina Gambato ◽

Maria Guarino ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Practice ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Critical Evaluation ◽

Real Life ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Immune Checkpoints

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises—advanced chronic liver disease—to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC.

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Cancer associated-fibroblast-derived exosomes in cancer progression

Molecular Cancer ◽

10.1186/s12943-021-01463-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Chao Li ◽

Adilson Fonseca Teixeira ◽

Hong-Jian Zhu ◽

Peter ten Dijke

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Chemotherapy Resistance ◽

Cell Types ◽

Cancer Therapies ◽

Cancer Associated Fibroblast

AbstractTo identify novel cancer therapies, the tumor microenvironment (TME) has received a lot of attention in recent years in particular with the advent of clinical successes achieved by targeting immune checkpoint inhibitors (ICIs). The TME consists of multiple cell types that are embedded in the extracellular matrix (ECM), including immune cells, endothelial cells and cancer associated fibroblasts (CAFs), which communicate with cancer cells and each other during tumor progression. CAFs are a dominant and heterogeneous cell type within the TME with a pivotal role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis and chemotherapy resistance. CAFs mediate their effects in part by remodeling the ECM and by secreting soluble factors and extracellular vesicles. Exosomes are a subtype of extracellular vesicles (EVs), which contain various biomolecules such as nucleic acids, lipids, and proteins. The biomolecules in exosomes can be transmitted from one to another cell, and thereby affect the behavior of the receiving cell. As exosomes are also present in circulation, their contents can also be explored as biomarkers for the diagnosis and prognosis of cancer patients. In this review, we concentrate on the role of CAFs-derived exosomes in the communication between CAFs and cancer cells and other cells of the TME. First, we introduce the multiple roles of CAFs in tumorigenesis. Thereafter, we discuss the ways CAFs communicate with cancer cells and interplay with other cells of the TME, and focus in particular on the role of exosomes. Then, we elaborate on the mechanisms by which CAFs-derived exosomes contribute to cancer progression, as well as and the clinical impact of exosomes. We conclude by discussing aspects of exosomes that deserve further investigation, including emerging insights into making treatment with immune checkpoint inhibitor blockade more efficient.

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An overview of immune checkpoint inhibitors in breast cancer

Exploration of Targeted Anti-tumor Therapy ◽

10.37349/etat.2020.00029 ◽

2020 ◽

Vol 1 (6) ◽

Author(s):

Federica Miglietta ◽

Maria Silvia Cona ◽

Maria Vittoria Dieci ◽

Valentina Guarneri ◽

Nicla La Verde

Keyword(s):

Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Immune Checkpoint Blockade ◽

Novel Treatment ◽

Near Future ◽

Triple Negative Subtype

Although breast cancer is not traditionally considered an immunogenic type of tumor, the combination of immunotherapy and chemotherapy has recently emerged as a novel treatment option in triple-negative subtype in the advanced setting and other similar combinations of immune checkpoint inhibitors with chemotherapy are expected to become part of the neoadjuvant management in the near future. In addition, encouraging results have been observed with the combination of immune checkpoint blockade with diverse biological agents, including anti-HER2 agents, CDK 4/6 inhibitors, PARP-inhibitors. The present review summarized the available evidence coming from clinical trials on the role of immune checkpoint inhibitors in the management of breast cancer, both in advanced and early setting.

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The Role of Molecular Profiling to Predict the Response to Immune Checkpoint Inhibitors in Lung Cancer

Cancers ◽

10.3390/cancers11020201 ◽

2019 ◽

Vol 11 (2) ◽

pp. 201 ◽

Cited By ~ 13

Author(s):

Courèche Kaderbhaï ◽

Zoé Tharin ◽

François Ghiringhelli

Keyword(s):

Lung Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Surrogate Marker ◽

Dna And Rna ◽

Tumor Mutational Burden ◽

Tumor Expression

Immune checkpoint inhibitors radically changed the treatment of patients with non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies when used as monotherapy. The assessment of Program Death Ligand-1 (PD-L1) tumor expression by immunohistochemistry is used to select potential responder patients, but this not an optimal marker since it does not predict the absence of anti PD-1 efficacy. Despite this shortcoming, PD-L1 remains the gold standard biomarker in many studies and the only biomarker available for clinicians. In addition to histological markers, transcriptomic and exome analyses have revealed potential biomarkers requiring further confirmation. Recently, tumor mutational burden has emerged as a good surrogate marker of outcome. In this review we will detail current knowledge on DNA and RNA related biomarkers.

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Lentiviral interferon with immune checkpoint blockade: A novel method for gene therapy in bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.33 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 33-33

Author(s):

Sharada Mokkapati ◽

Andrea Kokorovic ◽

Jonathan J. Duplisea ◽

Devin Plote ◽

Amy Lim ◽

...

Keyword(s):

Gene Therapy ◽

Bladder Cancer ◽

Combination Therapy ◽

Cell Viability ◽

Immune Checkpoint ◽

Target Genes ◽

Checkpoint Inhibitors ◽

Immune Checkpoint Blockade ◽

Control Virus

33 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. LV can infect non-dividing cells and integrate into the host’s genome, making it more efficient gene delivery vectors. As treatment with IFN upregulates checkpoint inhibitors, we also wanted to investigate the role of checkpoint inhibitors with and without IFN gene therapy. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα (MOI 2:1). IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, the MB49 intravesical tumor model and p53+/- C57/B6 mouse model were employed. We also assessed the role of combination therapy with immune checkpoint blockade using PD1 antibody using our MB49 intravesical model. Results: Efficient LV-IFNα transduction of BLCA cells resulted in increased expression of IFNα and its target genes and reduced cell viability vs. controls (p<0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase8 inhibition. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. Overall survival improved in the MB49 model and BBN model in treated mice. LV-IFN induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis in BBN model whereas in the MB49 tumor response was mediated by TRAIL. Combination therapy with PD1 resulted in further improved survival. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival in mouse models. Combining it with PD1 therapy appears to further improve survival.

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