The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage

2021 ◽  
Vol 118 (47) ◽  
pp. e2112674118
Author(s):  
Sarmishtha De ◽  
Elise G. Holvey-Bates ◽  
Kala Mahen ◽  
Belinda Willard ◽  
George R. Stark
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
E3 Ligase ◽  
Nonsmall Cell Lung Cancer ◽  
Immune Checkpoint Blockade ◽  
High Expression ◽  
Ubiquitin E3 Ligase ◽  
Programmed Death

High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al., Science 353, 399–403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.

scholarly journals Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 809 ◽  
Author(s):  
Kloten ◽  
Lampignano ◽  
Krahn ◽  
Schlange
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Tissue Samples ◽  
Programmed Death ◽  
Nsclc Patients

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

scholarly journals Understanding Checkpoint Inhibitors in Cancer Therapy, Mechanisms of Action, Resistance and Future Challenges

2020 ◽  
pp. 1-13
Author(s):  
Harman Saman ◽  
Harman Saman ◽  
Shahab Uddin ◽  
Syed Raza ◽  
Raj Shrimali ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Mechanisms Of Action ◽  
Programmed Death ◽  
Future Challenges

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 system by cancer cells mechanisms of action and successes of immune checkpoint inhibitors (ICI), particularly programmed death1 (PD-1) and programmed death-ligand (PD-L1) inhibitors as well as mechanisms that result in resistance of cancer cells to ICI.

scholarly journals Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zu Ye ◽  
Yin Shi ◽  
Susan P. Lees-Miller ◽  
John A. Tainer
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Dna Damage Response ◽  
Immune Checkpoint ◽  
B Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Dna Damage And Repair ◽  
Damage Response

The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially improved molecular and mechanistic understanding of how DDR components are interconnected to inflammatory and immune responses to stress. DDR shapes both innate and adaptive immune pathways: (i) in the context of innate immunity, DDR components mainly enhance cytosolic DNA sensing and its downstream STimulator of INterferon Genes (STING)-dependent signaling; (ii) in the context of adaptive immunity, the DDR is needed for the assembly and diversification of antigen receptor genes that is requisite for T and B lymphocyte development. Imbalances between DNA damage and repair impair tissue homeostasis and lead to replication and transcription stress, mutation accumulation, and even cell death. These impacts from DDR defects can then drive tumorigenesis, secretion of inflammatory cytokines, and aberrant immune responses. Yet, DDR deficiency or inhibition can also directly enhance innate immune responses. Furthermore, DDR defects plus the higher mutation load in tumor cells synergistically produce primarily tumor-specific neoantigens, which are powerfully targeted in cancer immunotherapy by employing immune checkpoint inhibitors to amplify immune responses. Thus, elucidating DDR-immune response interplay may provide critical connections for harnessing immunomodulatory effects plus targeted inhibition to improve efficacy of radiation and chemotherapies, of immune checkpoint blockade, and of combined therapeutic strategies.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Cai ◽  
Huajie Zhan ◽  
Yuguang Ye ◽  
Jinjin Yang ◽  
Minghui Zhang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Microbial Infection ◽  
Antiviral Immune Response

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.

scholarly journals Mass Spectrometry-Based Multivariate Proteomic Tests for Prediction of Outcomes on Immune Checkpoint Blockade Therapy: The Modern Analytical Approach

2020 ◽  
Vol 21 (3) ◽  
pp. 838 ◽  
Author(s):  
Julia Grigorieva ◽  
Senait Asmellash ◽  
Lelia Net ◽  
Maxim Tsypin ◽  
Heinrich Roder ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Machine Learning Techniques ◽  
Tumor Type ◽  
Multivariate Tests ◽  
Host Interactions ◽  
Additional Layer ◽  
Learning Techniques ◽  
Programmed Death

The remarkable success of immune checkpoint inhibitors (ICIs) has given hope of cure for some patients with advanced cancer; however, the fraction of responding patients is 15–35%, depending on tumor type, and the proportion of durable responses is even smaller. Identification of biomarkers with strong predictive potential remains a priority. Until now most of the efforts were focused on biomarkers associated with the assumed mechanism of action of ICIs, such as levels of expression of programmed death-ligand 1 (PD-L1) and mutation load in tumor tissue, as a proxy of immunogenicity; however, their performance is unsatisfactory. Several assays designed to capture the complexity of the disease by measuring the immune response in tumor microenvironment show promise but still need validation in independent studies. The circulating proteome contains an additional layer of information characterizing tumor–host interactions that can be integrated into multivariate tests using modern machine learning techniques. Here we describe several validated serum-based proteomic tests and their utility in the context of ICIs. We discuss test performances, demonstrate their independence from currently used biomarkers, and discuss various aspects of associated biological mechanisms. We propose that serum-based multivariate proteomic tests add a missing piece to the puzzle of predicting benefit from ICIs.

scholarly journals PD-1/PD-L1 Targeting in Breast Cancer: The First Clinical Evidences Are Emerging. A Literature Review

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1033 ◽  
Author(s):  
Planes-Laine ◽  
Rochigneux ◽  
Bertucci ◽  
Chrétien ◽  
Viens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Programmed Death ◽  
Tumor Types ◽  
Selection Of Patients ◽  
Selection Of ◽  
Triple Negative Subtype

Recently, the development of immunotherapy through the immune checkpoint blockade led to long-lasting responses in several types of cancers that are refractory to conventional treatments, such as melanoma or non-small cell lung cancer. Immunotherapy has also demonstrated significant improvements in various other types of cancers. However, breast cancer remains one of the tumors that have not experienced the explosion of immunotherapy yet. Indeed, breast cancer was traditionally considered as being weakly immunogenic with a lower mutational load compared to other tumor types. In the last few years, anti-PD1/PD-L1 (Programmed death-ligand 1) agents have been evaluated in breast cancer, particularly in the triple negative subtype, with promising results observed when delivered as monotherapy or in combination with conventional treatments. In this review, we will report the results of the most recent studies evaluating immune checkpoint inhibitors in breast cancer. In addition, we will discuss the concomitant development of possible biomarkers, which is required for improving the selection of patients with the highest probability of benefiting from these agents.

scholarly journals Toxicity of Immune-Checkpoint Inhibitors in Hematological Malignancies

2021 ◽  
Vol 12 ◽  
Author(s):  
Katarina Hradska ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Hematological Malignancies ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Programmed Death ◽  
Anti Cancer ◽  
Programmed Death 1 ◽  
Insight Into

Immune checkpoint inhibitors (ICIs), especially those targeting the programmed-death 1 (PD-1) receptor and its ligands, have become indispensable agents in solid tumor anti-cancer therapy. Concerning hematological malignancies, only nivolumab and pembrolizumab have been approved for the treatment of relapsed and refractory classical Hodgkin lymphoma and primary mediastinal large B cell lymphoma to date. Nevertheless, clinical research in this field is very active. The mechanism of action of ICIs is based on unblocking the hindered immune system to recognize and eliminate cancer cells, but that also has its costs in the form of ICI-specific immune related adverse events (irAEs), which can affect any organ system and can even be lethal. In this article, we have reviewed all prospective blood cancer clinical trials investigating ICIs (both monotherapy and combination therapy) with available toxicity data with the purpose of determining the incidence of irAEs in this specific setting and to offer a brief insight into their management, as the use of immune checkpoint blockade is not so frequent in hemato-oncology.

scholarly journals Combination of immunotherapy with chemotherapy and radiotherapy in lung cancer: is this the beginning of the end for cancer?

2018 ◽  
Vol 10 ◽  
pp. 175883591876209 ◽  
Author(s):  
Chiara Lazzari ◽  
Niki Karachaliou ◽  
Alessandra Bulotta ◽  
Mariagrazia Viganó ◽  
Aurora Mirabile ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Combination Strategies ◽  
Current Review ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Nsclc Patients ◽  
Sequential Evaluation

Immune checkpoint inhibitors have significantly improved overall survival with an acceptable safety profile in a substantial proportion of non-small cell lung cancer (NSCLC) patients. However, not all patients are sensitive to immune checkpoint blockade and, in some cases, programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors accelerate tumor progression. Several combination strategies are under evaluation, including the concomitant or sequential evaluation of chemotherapy or radiotherapy with immunotherapy. The current review provides an overview on the molecular rationale for the investigation of combinatorial approaches with chemotherapy or radiotherapy. Moreover, the results of completed clinical studies will be reported.

Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

2020 ◽  
Vol 20 (9) ◽  
pp. 720-727
Author(s):  
Jianguo Qiu ◽  
Wei Tang ◽  
Chengyou Du
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Immune Checkpoint ◽  
Graft Rejection ◽  
Checkpoint Inhibitors ◽  
Liver Graft ◽  
Immune Checkpoints ◽  
Term Survival ◽  
Liver Preservation ◽  
Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

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