The He laboratory can be supported by the National Institute of Health (grant 2K12CA133250)

The He laboratory can be supported by the National Institute of Health (grant 2K12CA133250). Notes Competing interests Carglumic Acid The authors declare to have no competing financial interests. Contributor Information Ning Zou, Email: moc.361@611gninynnus. Kai He, Email: ude.cmuso@eh.iak. Hua Zhu, Email: ude.cmuso@uhZ.auH.. application of their blocking antibodies in cancer treatment, and then discuss the cardiac toxicity induced by the therapy and the strategy to monitor, manage this adverse event when it occurs. strong class=”kwd-title” Keywords: cancer immunotherapy, immune checkpoint inhibitor, CTLA-4, PD-1, PD-L1, cardiac toxicity, myocarditis Introduction Cancer comprises a group of diseases in which cells divide uncontrollably, without following the normal process of cellular growth, proliferation and differentiation. Cancer cells undergo multiple mutations and express different antigens known as tumor-specific antigens (TSA). They also upregulate the expression of non-mutated molecules to abnormally high levels, referred to as tumor-associated antigens (TAA) [1]. Both TSA and TAA can be detected by the host immune system-activating downstream pathways that can eliminate cancer cells. Cancer cells are able to evade immune surveillance through overexpressing checkpoint proteins that Carglumic Acid prevent immune cells from killing them [2]. This process allows for them to survive and persist in the host [3]. To overcome this survival mechanism adopted by cancer cells, immunotherapy has emerged as a method to allow for the immune system to activate, recognize and attack neoplastic cells. Compared to the traditional surgical, chemotherapeutic or radiotherapeutic approaches, immunotherapy exhibits a more favorable toxicity profile while treating metastatic solid tumors systemically and provides clinical benefit with long-term disease control [4]. Immune-checkpoint inhibition is currently one of the most promising types of immunotherapy employed in cancer management. It has revolutionized the treatment of various malignancies including melanoma, non-small-cell lung cancer, renal cell carcinoma, Hodgkins lymphoma, bladder cancer, head Carglumic Acid and neck cancer, gastric cancer, liver cancer and microsatellite instability high or DNA mismatch repair-deficient colorectal cancer and solid tumors by improving the response rates and overall prognosis of cancer patients. Immune checkpoints are comprised of multiple inhibitory pathways that involve the interactions of co-receptors and ligands expressed on the surfaces of T cells and antigen-presenting cells. Once a T cell recognizes and binds to its cognate antigen through the T cell receptor (TCR), the interaction exerts a co-stimulatory or inhibitory downstream signaling to either suppress or activate the T cell. These co-stimulatory and inhibitory interactions also allow for the maintenance of self-tolerance under normal physiological conditions, preventing autoimmunity and tissue damage upon pathogenic insults [5]. In light of the immune tolerance that occurs within the tumor microenvironment, pharmaceutical companies have devoted significant efforts to develop drugs that block the immune checkpoints while activating the hosts immune system against cancer. Indeed, since the approval of ipilimumaba monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) by the Food and Drug Administration (FDA) in 2011the era of immunotherapy has emerged rapidly (a full list of FDA-approved checkpoint inhibitors is shown in Table?1). Following ipilimumab, two anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) and three anti-programmed cell Rabbit Polyclonal to PIK3CG death ligand (PD-L1) antibodies (atezolizumab, durvalumab, and avelumab) have also been developed and subsequently approved by the FDA for treatment of various metastatic solid tumors [6C9]. With the rapid emergence and use of the checkpoint inhibitors, a wide spectrum of immune-related adverse events (irAEs) has been documented [10C13]. Of all the irAEs, cardiovascular toxicity, although rare but potentially deadly, has not been well recognized or reported [11]. In this review, we will elaborate on the mechanisms and clinical applications of immune checkpoint inhibitors, focusing on CTLA-4 and PD-1/PD-L1 inhibitors and their associated autoimmune cardiotoxicity. We will discuss the preclinical modeling and clinical investigation of immunotherapy-induced cardiac adverse effects, the prophylactic strategies, and the potential treatments for checkpoint inhibitor-induced cardiotoxicity. Table 1 Summary of FDA-approved checkpoint inhibitors thead th rowspan=”1″ colspan=”1″ Name /th th rowspan=”1″ colspan=”1″ Target /th th rowspan=”1″ colspan=”1″ Trade name /th th rowspan=”1″ colspan=”1″ Company /th th rowspan=”1″ colspan=”1″ First approval year /th /thead IpilimumabCTLA-4YervoyBristol-Myers Squibb Co.2011PembrolizumabPD-1KeytrudaMerck & Co., Inc.2014NivolumabPD-1OpdivoBristol-Myers Squibb Co.2014AtezolizumabPD-L1TecentriqGenentech, Inc.2016AvelumabPD-L1BavencioEMD Serono, Inc.2017DurvalumabPD-L1ImfiniziAstraZeneca UK Limited2017 Open in a separate window Immune checkpoint therapy Role of co-stimulatory and co-inhibitory molecules The immune system performs the surveillance and clearance of transformed malignant cells. T lymphocytes, as a major component of the human immune system, play an essential role in both processes [14]. Once the T cell receptor recognizes a tumor antigen presented by.