Immuno-Metabolism: The Role of Cancer Niche in Immune Checkpoint Inhibitor Resistance

The use of immune checkpoint inhibitors (ICI) in treating cancer has revolutionized the approach to eradicate cancer cells by reactivating immune responses. However, only a subset of patients benefits from this treatment; the majority remains unresponsive or develops resistance to ICI therapy. Increasing evidence suggests that metabolic machinery in the tumor microenvironment (TME) plays a role in the development of ICI resistance. Within the TME, nutrients and oxygen are scarce, forcing immune cells to undergo metabolic reprogramming to adapt to harsh conditions. Cancer-induced metabolic deregulation in immune cells can attenuate their anti-cancer properties, but can also increase their immunosuppressive properties. Therefore, targeting metabolic pathways of immune cells in the TME may strengthen the efficacy of ICIs and prevent ICI resistance. In this review, we discuss the interactions of immune cells and metabolic alterations in the TME. We also discuss current therapies targeting cellular metabolism in combination with ICIs for the treatment of cancer, and provide possible mechanisms behind the cellular metabolic rewiring that may improve clinical outcomes.

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Immune Checkpoint Inhibitor Nephrotoxicity: Update 2020

Kidney360 ◽

10.34067/kid.0000852019 ◽

2020 ◽

Vol 1 (2) ◽

pp. 130-140 ◽

Cited By ~ 4

Author(s):

Shruti Gupta ◽

Frank B. Cortazar ◽

Leonardo V. Riella ◽

David E. Leaf

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Solid Organ Transplantation ◽

Treatment Strategies ◽

Solid Organ ◽

Diagnostic Uncertainty ◽

Patients With Cancer ◽

Underlying Malignancy

Immune checkpoint inhibitors (ICPIs) have transformed the landscape of oncology, but are associated with a variety of autoimmune adverse events, including AKI. ICPI-associated AKI (ICPI-AKI) is emerging as an increasingly frequent cause of AKI in patients with cancer, and poses unique diagnostic and management challenges to clinicians who care for these patients. In this review, we describe the incidence and risk factors for ICPI-AKI, including proton pump inhibitor use, CKD, and combination immunotherapy. We discuss the limitations of the various definitions used for ICPI-AKI in prior studies, and propose a novel classification system (definite, probable, and possible ICPI-AKI) that recognizes the diagnostic uncertainty inherent in many cases. We discuss the key clinicopathologic features and treatment strategies for ICPI-AKI, including the role of kidney biopsy versus empirical treatment with steroids. We also explore the under-studied area of ICPI use in the setting of solid organ transplantation, where nephrologists and oncologists must balance the risk of rejection versus treating the underlying malignancy. Finally, we summarize existing data on the role of ICPI rechallenge after an episode of ICPI-AKI.

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miRNA as a Modulator of Immunotherapy and Immune Response in Melanoma

Biomolecules ◽

10.3390/biom11111648 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1648

Author(s):

Mai-Huong Thi Nguyen ◽

Yueh-Hsia Luo ◽

An-Lun Li ◽

Jen-Chieh Tsai ◽

Kun-Lin Wu ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Cancer Progression ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Clinical Applicability ◽

Melanoma Patients

Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the reasons related to the resistance of melanoma to immune checkpoint inhibitors. Of note, miRNAs are the regulators of not only cancer progression but also of the response between cancer cells and immune cells. Investigation of miRNA functions within the tumor microenvironment have suggested that miRNAs could be considered as key partners in immunotherapy. Here, we reviewed the known mechanism by which melanoma induces resistance to immunotherapy and the role of miRNAs in immune responses and the microenvironment.

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Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00347-9 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Miaoqin Chen ◽

Shiman Hu ◽

Yiling Li ◽

Ting Ting Jiang ◽

Hongchuan Jin ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Cell Function ◽

Checkpoint Inhibitors ◽

Critical Role ◽

Tumor Control ◽

New Strategies

AbstractCancer immunotherapy especially immune checkpoint inhibition has achieved unprecedented successes in cancer treatment. However, there are many patients who failed to benefit from these therapies, highlighting the need for new combinations to increase the clinical efficacy of immune checkpoint inhibitors. In this review, we summarized the latest discoveries on the combination of nucleic acid-sensing immunity and immune checkpoint inhibitors in cancer immunotherapy. Given the critical role of nuclear acid-mediated immunity in maintaining the activation of T cell function, it seems that harnessing the nuclear acid-mediated immunity opens up new strategies to enhance the effect of immune checkpoint inhibitors for tumor control.

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The immunotherapy revolution in genitourinary malignancies

Immunotherapy ◽

10.2217/imt-2020-0054 ◽

2020 ◽

Vol 12 (11) ◽

pp. 819-831

Author(s):

Shruti U Gandhy ◽

Ravi A Madan ◽

Jeanny B Aragon-Ching

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Cell Cancer ◽

Treatment Modalities ◽

Metastatic Setting ◽

Cancer Types ◽

Therapeutic Cancer Vaccines ◽

Demonstrate Survival Benefit

Immune checkpoint inhibitor (ICI) therapy and therapeutic cancer vaccines have continued to demonstrate survival benefit and durable clinical response in patients with renal cell cancer, prostate cancer and bladder cancer, with limited responses in testicular cancer. The role of immunotherapy in combination with chemotherapy or other targeted therapies in the neo-adjuvant, adjuvant and metastatic setting is actively being explored. We describe the current immunotherapy-related treatment modalities approved for genitourinary cancers, focusing on immune checkpoint inhibitors, vaccines and other modalities, and highlight ongoing studies involving immunotherapy in these cancer types.

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Immune Checkpoints in Cancers: From Signaling to the Clinic

Cancers ◽

10.3390/cancers13184573 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4573

Author(s):

Céline Pisibon ◽

Amira Ouertani ◽

Corine Bertolotto ◽

Robert Ballotti ◽

Yann Cheli

Keyword(s):

Immune System ◽

Patient Outcomes ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Mechanisms Of Action ◽

Immune Checkpoints

The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints.

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Integrated Analysis of the Transcriptome Profile Reveals the Potential Roles Played by Long Noncoding RNAs in Immunotherapy for Sarcoma

Frontiers in Oncology ◽

10.3389/fonc.2021.690486 ◽

2021 ◽

Vol 11 ◽

Author(s):

Boran Pang ◽

Yongqiang Hao

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Human Cancer ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Cancer Types ◽

Inhibitor Resistance

BackgroundLong-term survival is still low for high-risk patients with soft tissue sarcoma treated with standard management options, including surgery, radiation, and chemotherapy. Immunotherapy is a promising new potential treatment paradigm. However, the application of immune checkpoint inhibitors for the treatment of patients with sarcoma did not yield promising results in a clinical trial. Therefore, there is a considerable need to identify factors that may lead to immune checkpoint inhibitor resistance.MethodsIn this study, we performed a bioinformatic analysis of The Cancer Genome Atlas (TCGA) to detect key long noncoding RNAs (lncRNAs) that were correlated with immune checkpoint inhibitory molecules in sarcoma. The expression levels of these lncRNAs and their correlation with patient prognosis were explored. The upstream long noncoding RNAs were also examined via 450K array data from the TCGA. The potential roles of these lncRNAs were further examined via KEGG and GO analysis using DAVID online software. Finally, the relationship between these lncRNAs and immune cell infiltration in tumors and their effect on immune checkpoint inhibitors were further explored.ResultsWe identified lncRNAs correlated with tumor cell immune evasion in sarcoma. The expression of these lncRNAs was upregulated and correlated with worse prognosis in sarcoma and other human cancer types. Moreover, low DNA methylation occupation of these lncRNA loci was detected. Negative correlations between DNA methylation and lncRNA expression were also found in sarcoma and other human cancer types. KEGG and GO analyses indicated that these lncRNAs correlated with immune evasion and negative regulation of the immune response in sarcoma. Finally, high expression of these lncRNAs correlated with more suppressive immune cell infiltration and reduced sensitivity to immune checkpoint inhibitors in sarcoma and other human cancer types.ConclusionOur results suggest that long noncoding RNAs confer immune checkpoint inhibitor resistance in human cancer. Further characterization of these lncRNAs may help to elucidate the mechanisms underlying immune checkpoint inhibitor resistance and uncover a novel therapeutic intervention point for immunotherapy.

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Cancer and Immune Checkpoint Inhibitor Treatment in the Era of SARS-CoV-2 Infection

Cancers ◽

10.3390/cancers12113383 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3383

Author(s):

Thilo Gambichler ◽

Judith Reuther ◽

Christina H. Scheel ◽

Laura Susok ◽

Peter Kern ◽

...

Keyword(s):

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Viral Infections ◽

Checkpoint Inhibitors ◽

Severe Infection ◽

Increased Risk ◽

Anti Cancer ◽

The Right ◽

Inhibitor Treatment

Whether cancer patients receiving immune checkpoint inhibitors (ICI) are at an increased risk of severe infection and mortality during the corona pandemic is a hotly debated topic that will continue to evolve. Here, we summarize and discuss current studies regarding COVID-19 and anti-cancer treatment with an emphasis on ICI. Importantly, several lines of evidence suggest that patients currently treated with ICI do not display an increased vulnerability to infection with SARS-CoV-2. Data regarding morbidity and mortality associated with COVID-19 in cancer patients receiving ICI are less clear and often conflicting. Although mostly based on experimental data, it is possible that ICI can promote the exacerbated immune response associated with adverse outcome in COVID-19 patients. On the other hand, mounting evidence suggests that ICI might even be useful in the treatment of viral infections by preventing or ameliorating T cell exhaustion. In this context, the right timing of treatment might be essential. Nevertheless, some cancer patients treated with ICI experience autoimmune-related side effects that require the use of immunosuppressive therapies, which in turn may promote a severe course of infection with SARS-CoV-2. Although there is clear evidence that withholding ICI will have more serious consequences, further studies are urgently needed in to better evaluate the effects of ICI in patients with COVID-19 and the use of ICI during the corona pandemic in general.

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Immune Checkpoint Inhibitors: Basics and Challenges

Current Medicinal Chemistry ◽

10.2174/0929867324666170804143706 ◽

2019 ◽

Vol 26 (17) ◽

pp. 3009-3025 ◽

Cited By ~ 8

Author(s):

Bin Li ◽

Ho Lam Chan ◽

Pingping Chen

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Complete Response ◽

Modern World ◽

Basic Principles ◽

Mutation Status ◽

Anti Cancer ◽

Cancer Types ◽

Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

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The Role of PET/CT in the Era of Immune Checkpoint Inhibitors: State of Art

Current Radiopharmaceuticals ◽

10.2174/1874471012666191015100106 ◽

2020 ◽

Vol 13 (1) ◽

pp. 24-31 ◽

Cited By ~ 2

Author(s):

Angelo Castello ◽

Egesta Lopci

Keyword(s):

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Evaluation Criteria ◽

Advanced Melanoma ◽

Response Criteria ◽

Response Evaluation ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Background: Immune checkpoint inhibitors (ICI) have achieved astonishing results and improved overall survival (OS) in several types of malignancies, including advanced melanoma. However, due to a peculiar type of anti-cancer activity provided by these drugs, the response patterns during ICI treatment are completely different from that with “old” chemotherapeutic agents. Objective: To provide an overview of the available literature and potentials of 18F-FDG PET/CT in advanced melanoma during the course of therapy with ICI in the context of treatment response evaluation. Methods: Morphologic criteria, expressed by Response Evaluation Criteria in Solid Tumors (RECIST), immune-related response criteria (irRC), irRECIST, and, more recently, immune-RECIST (iRECIST), along with response criteria based on the metabolic parameters with 18F-Fluorodeoxyglucose (18FFDG), have been explored. Results: To overcome the limits of traditional response criteria, new metabolic response criteria have been introduced on time and are being continuously updated, such as the PET/CT Criteria for the early prediction of Response to Immune checkpoint inhibitor Therapy (PECRIT), the PET Response Evaluation Criteria for Immunotherapy (PERCIMT), and “immunotherapy-modified” PET Response Criteria in Solid Tumors (imPERCIST). The introduction of new PET radiotracers, based on monoclonal antibodies combined with radioactive elements (“immune-PET”), are of great interest. Conclusion: Although the role of 18F-FDG PET/CT in malignant melanoma has been widely validated for detecting distant metastases and recurrences, evidences in course of ICI are still scarce and larger multicenter clinical trials are needed.

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