Prospects for the use of small interfering RNAs as inhibitors of immune checkpoints for immunotherapy in oncology

Immune therapy is one of the most promising areas of cancer treatment. It is aimed at a cascade of processes responsible for the antitumor immune response. The involved regulatory mechanisms become targets for various therapeutic approaches aimed at restoring the impaired functions of immune cells that eliminate cancer cells. The ability of malignant cells to affect receptors of immune checkpoints is one of the most important mechanisms for suppressing antitumor immunity. The development of immune check-point inhibitors (ICIs) based on monoclonal antibodies, as well as the methods of adoptive cell therapy (ACT), are a breakthrough in the immunotherapy of malignant diseases, but it carries a number of limitations such as insufficient efficiency, safety and cost-effectiveness. The use of RNA interference technologies opens up prospects for the development of fundamentally new class of ICIs and, as a consequence, the development of more efficient ACT methods. This review presents the main problems and prospects of the use of small interfering RNA (siRNA) as the ICIs are highlighted in order to optimize modern AKT approaches

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Recent advances in understanding antitumor immunity

F1000Research ◽

10.12688/f1000research.9356.1 ◽

2016 ◽

Vol 5 ◽

pp. 2545 ◽

Cited By ~ 9

Author(s):

Rodrigo Ramella Munhoz ◽

Michael Andrew Postow

Keyword(s):

Immune Responses ◽

Antitumor Immunity ◽

Adoptive Cell Therapy ◽

Immune Checkpoints ◽

Tumor Control ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Recent Advances ◽

Open Questions

The term “antitumor immunity” refers to innate and adaptive immune responses which lead to tumor control. Turning the immune system into a destructive force against tumors has been achieved in a broad range of human cancers with the use of non-specific immunotherapies, vaccines, adoptive-cell therapy, and, more recently with significant success, through blockade of immune checkpoints. Nevertheless, the efficacy of these approaches is not universal, and tools to identify long-term responders and primarily refractory patients are warranted. In this article, we review recent advances in understanding the complex mechanisms of antitumor immunity and how these developments can be used to address open questions in a setting of growing clinical indications for the use of immunotherapy.

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The role of lncRNAs and circRNAs in the PD-1/PD-L1 pathway in cancer immunotherapy

Molecular Cancer ◽

10.1186/s12943-021-01406-7 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Wenxiao Jiang ◽

Shuya Pan ◽

Xin Chen ◽

Zhi-wei Wang ◽

Xueqiong Zhu

Keyword(s):

Cancer Immunotherapy ◽

Tumor Cells ◽

Antitumor Immunity ◽

Immune Therapy ◽

Noncoding Rnas ◽

Immune Checkpoints ◽

Circular Rnas ◽

Antitumor Effects ◽

Antitumor Immunotherapy

AbstractCancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

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Immune Checkpoint Inhibitor (ICPI) induced Nephrotoxicity – An Insight.

JMS SKIMS ◽

10.33883/jms.v23i3.774 ◽

2020 ◽

Vol 23 (3) ◽

Author(s):

Mohmad Hussian Mir ◽

Tariq Ahmad Bhat ◽

Khalid Parvez Sofi ◽

Imtiyaz Ahmad Wani ◽

Muzafar Maqsood Wani

Keyword(s):

Acute Kidney Injury ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Kidney Injury ◽

Check Point ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

New Class ◽

Transplant Patients ◽

Check Point Inhibitors

Immune check point inhibitors (ICPIs) are a new class of anti-neoplastic agents being increasingly used by oncologists to treat various malignancies. These drugs have been associated with varied side effects and have a nephrotoxic potential. Many cases of ICPI induced acute kidney injury are increasingly being reported. Their use in CKD patients on dialysis as well as in kidney transplant recipients is associated with various challenges. This review discusses the use of ICPIs in CKD, dialysis and renal transplant patients and their nephrotoxic potential

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A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints

Biomaterials Science ◽

10.1039/d0bm02210a ◽

2021 ◽

Author(s):

Yanlin Du ◽

Da Zhang ◽

Yiru Wang ◽

Ming Wu ◽

Cuilin Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Antitumor Immunity ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Immune Checkpoints

A highly stable multifunctional aptamer was prepared for strengthening antitumor immunity through a dual immune checkpoint blockade of CTLA-4 and PD-L1.

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Hsp70 Interacts with the TREM-1 Receptor Expressed on Monocytes and Thereby Stimulates Generation of Cytotoxic Lymphocytes Active against MHC-Negative Tumor Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22136889 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6889

Author(s):

Tatiana N. Sharapova ◽

Elena A. Romanova ◽

Olga K. Ivanova ◽

Denis V. Yashin ◽

Lidia P. Sashchenko

Keyword(s):

Innate Immunity ◽

Tumor Cells ◽

Heat Shock Protein 70 ◽

Antitumor Immunity ◽

Lymphocyte Subpopulations ◽

Regulatory Mechanisms ◽

Cytotoxic Lymphocytes ◽

Special Significance ◽

Cytotoxic Lymphocyte ◽

Negative Tumor

The search for and analysis of new ligands for innate immunity receptors are of special significance for understanding the regulatory mechanisms of immune response. Here we show that the major heat shock protein 70 (Hsp70) can bind to and activate TREM-1, the innate immunity receptor expressed on monocytes. The Hsp70–TREM-1 interaction activates expression of TNFα and IFNγ mRNAs in monocytes and stimulates IL-2 secretion by РВМСs. Moreover, incubation of РВМСs with Hsp70 leads to an appearance of cytotoxic lymphocyte subpopulations active against the MHC-negative tumor cells. In addition, both the CD4+ Т-lymphocytes and CD14+ monocytes are necessary for the Hsp70 signal transduction and a consequent activation of the cytotoxic lymphocytes. We believe that data presented in this study will broaden the views on the involvement of Hsp70 in the antitumor immunity.

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Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade

Science Translational Medicine ◽

10.1126/scitranslmed.aak9670 ◽

2017 ◽

Vol 9 (385) ◽

pp. eaak9670 ◽

Cited By ~ 191

Author(s):

Martina Schmittnaegel ◽

Nicolò Rigamonti ◽

Ece Kadioglu ◽

Antonino Cassará ◽

Céline Wyser Rmili ◽

...

Keyword(s):

Antitumor Immunity ◽

Antiangiogenic Therapy ◽

Metastatic Breast ◽

Pancreatic Neuroendocrine Tumor ◽

Genetically Engineered ◽

Immune Checkpoints ◽

Tumor Control ◽

Antitumoral Activity ◽

Therapeutic Benefits ◽

Angiopoietin 2

Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-γ (IFNγ)–expressing CD8+ cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNγ neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy.

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Immune Deregulation in Sepsis and Septic Shock: Reversing Immune Paralysis by Targeting PD-1/PD-L1 Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2020.624279 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuki Nakamori ◽

Eun Jeong Park ◽

Motomu Shimaoka

Keyword(s):

Clinical Trials ◽

T Lymphocytes ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Specific Treatment ◽

Multiple Organ ◽

Lymphoid Cells ◽

Immune Checkpoints ◽

Drug Candidates ◽

Immune Paralysis

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

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Nanoparticle-enhanced chemo-immunotherapy to trigger robust antitumor immunity

Science Advances ◽

10.1126/sciadv.abc3646 ◽

2020 ◽

Vol 6 (35) ◽

pp. eabc3646 ◽

Cited By ~ 1

Author(s):

Jingjing Liang ◽

Huifang Wang ◽

Wenxiu Ding ◽

Jianxiang Huang ◽

Xuefei Zhou ◽

...

Keyword(s):

Triblock Copolymer ◽

Rational Design ◽

Antitumor Immunity ◽

Chemotherapeutic Agent ◽

Therapeutic Benefit ◽

Combination Regimen ◽

Cross Presentation ◽

New Class ◽

Immunosuppressive Tumor Microenvironment ◽

Novel Strategy

Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.

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Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

International Journal of Molecular Sciences ◽

10.3390/ijms21176176 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6176 ◽

Cited By ~ 1

Author(s):

Yolla Haibe ◽

Ziad El Husseini ◽

Rola El Sayed ◽

Ali Shamseddine

Keyword(s):

Immune Checkpoint ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Immune Checkpoints ◽

Therapeutic Approaches ◽

Standard Chemotherapy ◽

Primary Resistance ◽

In The Beginning ◽

Tumor Types

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

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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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