A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy (original) (raw)
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Hallmarks of Resistance to Immune-Checkpoint Inhibitors
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Lessons learned from the blockade of immune checkpoints in cancer immunotherapy
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The advent of immunotherapy, especially checkpoint inhibitor-based immunotherapy, has provided novel and powerful weapons against cancer. Because only a subset of cancer patients exhibit durable responses, further exploration of the mechanisms underlying the resistance to immunotherapy in the bulk of cancer patients is merited. Such efforts may help to identify which patients could benefit from immune checkpoint blockade. Given the existence of a great number of pathways by which cancer can escape immune surveillance, and the complexity of tumor-immune system interaction, development of various combination therapies, including those that combine with conventional therapies, would be necessary. In this review, we summarize the current understanding of the mechanisms by which resistance to checkpoint blockade immunotherapy occurs, and outline how actionable combination strategies may be derived to improve clinical outcomes for patients.
Drug Resistance Updates, 2020
Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases. However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer. While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host. Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed. Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3γ or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance. This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance. 1. State of the art in cancer immunotherapy Cancer incidence and mortality are rapidly growing worldwide. Freddie Bray and colleagues (Bray et al., 2018) reported more than 17.0 million new diagnosed cases and 9.6 million cancer deaths in 2018. Provided that both cancer incidence and mortality are highly associated with social and life style factors and related to the degree of economic development in each country (Allemani et al., 2018), there is a clear need to continue working in new strategies that improve these determinants. In this respect, intrinsic and acquired multidrug resistance (MDR) to various chemotherapeutic agents constitute a major impediment towards curative cancer treatment. These mechanisms of chemoresistance are often mediated: (i) via transmembrane efflux pumps of the ATP-binding cassette (ABC transporter) family that extrude a plethora of structurally and mechanistically distinct anticancer drugs; or (ii) via MDR efflux pump independent determinants.
Clinical Oncology and Research, 2020
The immune system is the human body’s natural defence against mutated cells produced as the result of DNA replicative error or by the effect of carcinogens, a process rereferred to as immune surveillance. ‘Escaping’ of cancer cells from immune surveillance leads to tumor development, metastasis and progression. Avoiding detection and destruction by the immune system are the result of cancer cells evolution, caused primarily by cancer cells’ genomic instability. On the other hand, scientists attempted for decades to exploit the anticancer effect of the immune system with limited success. However, better understanding of the mechanisms behind the cancer cells’ ability to avoid detection and suppression by the immune system resulted in the development of immune checkpoint inhibitors, a form of immunotherapy, first approved by the Food and Drug Administration (FDA) in 2011. This article reviews the pathways involved in anticancer immune response, evading and supressing of the immune sys...
Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier
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Recently, immune checkpoint inhibitors (ICIs) therapy has become a promising therapeutic strategy with encouraging therapeutic outcomes due to their durable anti-tumor effects. Though, tumor inherent or acquired resistance to ICIs accompanied with treatment-related toxicities hamper their clinical utility. Overall, about 60-70% of patients (e.g., melanoma and lung cancer) who received ICIs show no objective response to intervention. The resistance to ICIs mainly caused by alterations in the tumor microenvironment (TME), which in turn, supports angiogenesis and also blocks immune cell antitumor activities, facilitating tumor cells' evasion from host immunosurveillance. Thereby, it has been supposed and also validated that combination therapy with ICIs and other therapeutic means, ranging from chemoradiotherapy to targeted therapies as well as cancer vaccines, can capably compromise tumor resistance to immune checkpoint blocked therapy. Herein, we have focused on the therapeutic benefits of ICIs as a groundbreaking approach in the context of tumor immunotherapy and also deliver an overview concerning the therapeutic influences of the addition of ICIs to other modalities to circumvent tumor resistance to ICIs.
Editorial: Cancer Immunotherapies: From Efficacy to Resistance Mechanisms
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Editorial on the Research Topic Cancer Immunotherapies: From Efficacy to Resistance Mechanisms Current generations of cancer immunotherapies are used to abrogate immunosuppression or modify immune cells to enhance anti-tumor immune cell functions. With recent advances in antibody generation, characterization and production, the development of monoclonal antibodybased immunotherapies targeting co-inhibitory receptors on T cells, the so-called "immune checkpoint blockade (ICB)", has fundamentally changed the outlook on metastatic cancer and has offered new hope to patients for long-term survival. Despite their success, the clinical efficiencies of these treatments remain low and vary across different malignant diseases, sparking effort from the community to identify mechanisms responsible for therapy resistance and to offer a rationale for combination therapies aiming to further improve patient prognosis and outcomes. Under the theme "Cancer Immunotherapies: from efficacy to resistance mechanisms", 41 articles covering a wide range of topics in cancer immunotherapy were contributed. Here, we highlight the most valuable insights from original research articles and reviews published in this issue.
Tumor immunotherapies by immune checkpoint inhibitors (ICIs); the pros and cons
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The main breakthrough in tumor immunotherapy was the discovery of immune checkpoint (IC) proteins, which act as a potent suppressor of the immune system by a myriad of mechanisms. After that, scientists focused on the immune checkpoint molecules mainly. Thereby, much effort was spent to progress novel strategies for suppressing these inhibitory axes, resulting in the evolution of immune checkpoint inhibitors (ICIs). Then, ICIs have become a promising approach and shaped a paradigm shift in tumor immunotherapies. CTLA-4 plays an influential role in attenuation of the induction of naïve and memory T cells by engagement with its responding ligands like B7-1 (CD80) and B7-2 (CD86). Besides, PD-1 is predominantly implicated in adjusting T cell function in peripheral tissues through its interaction with programmed death-ligand 1 (PD-L1) and PD-L2. Given their suppressive effects on anti-tumor immunity, it has firmly been documented that ICIs based therapies can be practical and rational therapeutic approaches to treat cancer patients. Nonetheless, tumor inherent or acquired resistance to ICI and some treatment-related toxicities restrict their application in the clinic. The current review will deliver a comprehensive overview of the ICI application to treat human tumors alone or in combination with other modalities to support more desired outcomes and lower toxicities in cancer patients.
Immune checkpoints inhibitors in cancer therapy-current status and future prospects
International journal of health sciences
The field of oncology is revolutionized by immunotherapy. immunotherapy is a fundamental breakthrough in cancer treatment that focuses on boosting the natural defense for malignant cell elimination. Cancer immunotherapy is of different forms including, virus therapies, adoptive cell transfer, cytokine therapies, immune checkpoint inhibitors, and cancer vaccines, all of which have promise future developments and clinical applications. To maintain homeostasis several pathways of immune signaling are employed that inhibit or stimulate immune responses. These immune signaling pathways help to keep immune responses maintained by avoiding autoimmunity and chronic inflammation, these immune signals that regulate immune responses in the body are also known as immune checkpoints. The responses of numerous self-regulating checkpoints of the immune system are exploited by the cancerous cells. Immune checkpoint inhibitors and monoclonal antibodies (mAbs) are becoming the most important immunoth...