scholarly journals Palmitoylation is critically required for cancer intrinsic PD-1 expression and functions

2019 ◽  
Author(s):  
Han Yao ◽  
Chushu Li ◽  
Jean-Philippe Brosseau ◽  
Huanbin Wang ◽  
Haojie Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Competitive Inhibitor ◽  
Recycling Endosome ◽  
Downstream Signaling ◽  
Anticancer Target ◽  
First Time ◽  
Cell Death Protein

AbstractProgrammed cell death protein 1 (PD-1) is a crucial anticancer target, but the relatively low response rate and acquired resistance to existing antibody drugs highlight an urgent need to develop alternative targeting strategies. Here we report the palmitoylation of PD-1, discovered the main DHHC enzyme for this modification, revealed the mechanism for its effect on PD-1 expression, and rationally developed a peptide for targeting PD-1 expression. Palmitoylation promoted the trafficking of PD-1 to recycling endosome, thus preventing its lysosome-dependent degradation. Palmitoylation was required for the activation of PD-1 downstream signaling, and targeting palmitoylation by pharmacological inhibitor or depleting the modification enzyme caused significant anti-tumor effects. A peptide was designed to competitively inhibit PD-1 palmitoylation and expression, opening a new route for developing PD-1 inhibitors as a strategy for cancer immunotherapy.SignificanceWe show for the first time that PD-1 is palmitoylated, identify DHHC9 as the predominant enzyme for its palmitoylation, and reveal the molecular mechanisms underlying its effects on PD-1 stability and functions. Importantly, we also designed a competitive inhibitor targeting PD-1 palmitoylation, and this first-in-class molecule may inspire the development of new checkpoint inhibitors.

Impact of KRAS mutational variant on response to immunotherapy in metastatic NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21127-e21127
Author(s):  
Shelley Kuang ◽  
Sally C. M. Lau ◽  
Kieran Sharma ◽  
Juehea Lee ◽  
Malcolm Isaiah Ryan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Overall Response Rate ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Response To Therapy ◽  
Smoking History ◽  
Driver Mutations ◽  
Lung Cancers ◽  
Overall Response ◽  
Downstream Signaling

e21127 Background: KRAS alterations constitute the most common driver mutations in metastatic non-small cell lung cancers (mNSCLC) and occur in approximately 30% of patients. KRAS mutational subtype as well as the presence of co-mutations has been associated with altered activation of downstream signaling pathways in preclinical models. We hypothesize that different KRAS G12C mutational subsets will be associated with variable clinical outcome and response to therapy. To this end, we have performed a retrospective analysis of survival and treatment outcomes by KRAS mutation subtype (G12C vs non-G12C). Methods: A review of KRAS-mutated mNSCLC patients treated with immunotherapy between 2013 and 2020 was conducted. Patient demographics, smoking status, KRAS mutational subtype, co-mutations and PD-L1 status were collected. Overall response rate (ORR) and progression-free survival (PFS) were analyzed in each subgroup. Results: 98 KRAS mutant mNSCLC patients were treated with immune checkpoint inhibitors (ICI): 37% with a KRAS G12C mutation, 62% with a non-G12C mutation. Patients with a G12C mutation were more likely to be of Caucasian ancestry (86% vs 56%; p = 0.01) whereas all other characteristics were similar between the groups including smoking history, PD-L1 expression ≥50% (61% vs 40%) and the presence of a TP53 co-mutation (48% vs. 54%); all p > 0.05. Treatment patterns were similar between the groups, with PD-1 inhibitor monotherapy given in 86% vs 79% of KRAS G12C and non-G12C patients. Overall response rate was 51% vs 27% in G12C vs non-G12C (p = 0.03). PFS was superior in G12C mutants (19.6 months vs 4.0 months), even after adjusting for smoking history, TP53 co-mutation status and PD-L1 expression (adjusted HR 0.51; p = 0.02). In subgroup analyses, the superiority in PFS was driven by the G12C mutants with high PD-L1 expression (n = 19): 26.8 months in G12C, PD-L1 high vs 4.7 months in G12C, PD-L1 low vs. 4.7 months in KRAS transversion mutations, PD-L1 high vs 4.0 months in transversion mutations, PD-L1 low vs. 3.0 months in transition mutations; p < 0.001. Conclusions: The presence of a KRAS G12C mutation is associated with improved ORR and PFS after treatment with ICI compared to non-G12C mutations in mNSCLC. The greatest benefit in PFS was observed in the subgroup with G12C mutation and high PD-L1 expression. Differential activation of downstream signaling associated with specific KRAS codon 12 mutation variants may modulate the composition of the tumor immune microenvironment thereby contributing to the variable response to immunotherapy. Further understanding on these molecular mechanisms may direct the development of new treatment strategies in KRAS mutant lung cancers.

scholarly journals A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions

2021 ◽  
Author(s):  
Han Yao ◽  
Chushu Li ◽  
Fang He ◽  
Teng Song ◽  
Jean-Philippe Brosseau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Competitive Inhibitor ◽  
First Time

We show for the first time that PD-1 is palmitoylated, identify DHHC9 as the predominant enzyme for its palmitoylation, and reveal the molecular mechanisms underlying its effects on PD-1 stability and functions. Importantly, we also designed PD1-PALM, a competitive inhibitor of PD-1 palmitoylation, and this first-in-class molecule may inspire the development of new checkpoint inhibitors.

scholarly journals Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6176 ◽  
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.

scholarly journals The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Cristina Vajaitu ◽  
Carmen Cristina Draghici ◽  
Iulia Solomon ◽  
Cristina Victoria Lisievici ◽  
Alexandra Victoria Popa ◽  
...  
Keyword(s):  
Response Rate ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Overall Survival Rate ◽  
Small Cell Lung ◽  
Cancer And Inflammation ◽  
Cell Death Protein ◽  
Free Rate

An important function of the immune system is its ability to differentiate between healthy cells in the organism and “foreign” cells, allowing the latest to be attacked and the first ones to be conserved. The most important molecules in this process are considered to be checkpoint inhibitors. This review is focused on the association between cancer and inflammation, underlying the mechanisms of action of monoclonal antibodies that are targeting checkpoint inhibitors: ipilimumab against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and pembrolizumab and nivolumab against programmed cell death protein 1 (PD-1), their indications for treatment, and side effects. Presence of antibodies against checkpoint inhibitors shows promising results in the clinical trials in patients with types of cancer difficult to treat until now such as melanoma, non-small-cell lung cancer (NSCLC), and renal cell carcinoma, offering an increase in the overall survival rate, response rate, and progression-free rate. Resistance is now observed to emerge in patients treated with this therapy, showing the need for more studies in order to design a biomarker that will predict the type of response to immunotherapy.

scholarly journals Molecular Mechanisms of Resistance to Immune Checkpoint Inhibitors in Melanoma Treatment: An Update

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 835
Author(s):  
Sonja Vukadin ◽  
Farah Khaznadar ◽  
Tomislav Kizivat ◽  
Aleksandar Vcev ◽  
Martina Smolic
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Significant Proportion ◽  
Resistance Mechanisms ◽  
Advanced Melanoma ◽  
Mutational Status ◽  
Primary Drug Resistance

Over the past decade, immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma and ensured significant improvement in overall survival versus chemotherapy. ICI or targeted therapy are now the first line treatment in advanced melanoma, depending on the tumor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutational status. While these new approaches have changed the outcomes for many patients, a significant proportion of them still experience lack of response, known as primary resistance. Mechanisms of primary drug resistance are not fully elucidated. However, many alterations have been found in ICI-resistant melanomas and possibly contribute to that outcome. Furthermore, some tumors which initially responded to ICI treatment ultimately developed mechanisms of acquired resistance and subsequent tumor progression. In this review, we give an overview of tumor primary and acquired resistance mechanisms to ICI and discuss future perspectives with regards to new molecular targets and combinatorial therapies.

TAMM HORSFALL PROTEIN: THE MEN BEHIND THE EPONYM

2019 ◽  
Vol 23 (2) ◽  
pp. 117-119 ◽  
Author(s):  
D. N. Paskalev ◽  
B. T. Galunska ◽  
D. Petkova-Valkova
Keyword(s):  
Viral Replication ◽  
Research Team ◽  
Molecular Mechanisms ◽  
Thick Ascending Limb ◽  
Rockefeller Institute ◽  
The Usa ◽  
Natural Inhibitor ◽  
Simplex Virus ◽  
First Time ◽  
New Protein

Tamm–Horsfall Protein (uromodulin) is named after Igor Tamm and Franc Horsfall Jr who described it for the first time in 1952. It is a glycoprotein, secreted by the cells in the thick ascending limb of the loop of Henle. This protein will perform a number of important pathophysiological functions, including protection against uroinfections, especially caused by E. Сoli, and protection against formation of calcium concernments in the kidney. Igor Tamm (1922-1995) is an outstanding cytologist, virologist and biochemist. He is one of the pioneers in the study of viral replication. He was born in Estonia and died in the USA. In 1964 he was elected for a professorship in Rockefeller Institute for Medical Research, where has been working continuously. Since 1959, he became a head of the virology lab established by his mentor and co-author Franc Horsfall. In the course of studies on the natural inhibitor of viral replication, Tamm and Horsfall isolated and characterized biochemically a new protein named after their names. Franc Lappin Horsfall Jr (1906-1971) was a well-known clinician and virologist with remarkable achievements in internal medicine. He was born and died in the USA. He worked in the Rockefeller Hospital from 1934 to 1960, then in the Center for Cancer Research at the Sloan-Kettering Institute. Here he was a leader of a research team studying the molecular mechanisms of immunity, the effects of chemotherapy with benzimidazole compounds (together with I. Tamm), coxsackie viruses, herpes simplex virus, etc. 

Radio-Susceptibility of Nasopharyngeal Carcinoma: Focus on Epstein- Barr Virus, MicroRNAs, Long Non-Coding RNAs and Circular RNAs

2020 ◽  
Vol 13 (3) ◽  
pp. 192-205 ◽  
Author(s):  
Fanghong Lei ◽  
Tongda Lei ◽  
Yun Huang ◽  
Mingxiu Yang ◽  
Mingchu Liao ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Regulatory Networks ◽  
Epstein Barr Virus ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Circular Rnas ◽  
Barr Virus ◽  
Non Coding Rnas ◽  
Epstein Barr

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer. As a neoplastic disorder, NPC is a highly malignant squamous cell carcinoma that is derived from the nasopharyngeal epithelium. NPC is radiosensitive; radiotherapy or radiotherapy combining with chemotherapy are the main treatment strategies. However, both modalities are usually accompanied by complications and acquired resistance to radiotherapy is a significant impediment to effective NPC therapy. Therefore, there is an urgent need to discover effective radio-sensitization and radio-resistance biomarkers for NPC. Recent studies have shown that Epstein-Barr virus (EBV)-encoded products, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which share several common signaling pathways, can function in radio-related NPC cells or tissues. Understanding these interconnected regulatory networks will reveal the details of NPC radiation sensitivity and resistance. In this review, we discuss and summarize the specific molecular mechanisms of NPC radio-sensitization and radio-resistance, focusing on EBV-encoded products, miRNAs, lncRNAs and circRNAs. This will provide a foundation for the discovery of more accurate, effective and specific markers related to NPC radiotherapy. EBVencoded products, miRNAs, lncRNAs and circRNAs have emerged as crucial molecules mediating the radio-susceptibility of NPC. This understanding will improve the clinical application of markers and inform the development of novel therapeutics for NPC.

scholarly journals Integration of tumor inflammation, cell proliferation, and traditional biomarkers improves prediction of immunotherapy resistance and response

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sarabjot Pabla ◽  
R. J. Seager ◽  
Erik Van Roey ◽  
Shuang Gao ◽  
Carrie Hoefer ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Cell Activation ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Host Immune Response ◽  
Gene Signature ◽  
B Cell Activation ◽  
Rna Seq ◽  
Multiple Tumor

Abstract Background Contemporary to the rapidly evolving landscape of cancer immunotherapy is the equally changing understanding of immune tumor microenvironments (TMEs) which is crucial to the success of these therapies. Their reliance on a robust host immune response necessitates clinical grade measurements of immune TMEs at diagnosis. In this study, we describe a stable tumor immunogenic profile describing immune TMEs in multiple tumor types with ability to predict clinical benefit from immune checkpoint inhibitors (ICIs). Methods A tumor immunogenic signature (TIGS) was derived from targeted RNA-sequencing (RNA-seq) and gene expression analysis of 1323 clinical solid tumor cases spanning 35 histologies using unsupervised analysis. TIGS correlation with ICI response and survival was assessed in a retrospective cohort of NSCLC, melanoma and RCC tumor blocks, alone and combined with TMB, PD-L1 IHC and cell proliferation biomarkers. Results Unsupervised clustering of RNA-seq profiles uncovered a 161 gene signature where T cell and B cell activation, IFNg, chemokine, cytokine and interleukin pathways are over-represented. Mean expression of these genes produced three distinct TIGS score categories: strong (n = 384/1323; 29.02%), moderate (n = 354/1323; 26.76%), and weak (n = 585/1323; 44.22%). Strong TIGS tumors presented an improved ICI response rate of 37% (30/81); with highest response rate advantage occurring in NSCLC (ORR = 36.6%; 16/44; p = 0.051). Similarly, overall survival for strong TIGS tumors trended upward (median = 25 months; p = 0.19). Integrating the TIGS score categories with neoplastic influence quantified via cell proliferation showed highly proliferative and strong TIGS tumors correlate with significantly higher ICI ORR than poorly proliferative and weak TIGS tumors [14.28%; p = 0.0006]. Importantly, we noted that strong TIGS and highly [median = not achieved; p = 0.025] or moderately [median = 16.2 months; p = 0.025] proliferative tumors had significantly better survival compared to weak TIGS, highly proliferative tumors [median = 7.03 months]. Importantly, TIGS discriminates subpopulations of potential ICI responders that were considered negative for response by TMB and PD-L1. Conclusions TIGS is a comprehensive and informative measurement of immune TME that effectively characterizes host immune response to ICIs in multiple tumors. The results indicate that when combined with PD-L1, TMB and cell proliferation, TIGS provides greater context of both immune and neoplastic influences on the TME for implementation into clinical practice.

scholarly journals Nonclinical Development of SRK-181: An Anti-Latent TGFβ1 Monoclonal Antibody for the Treatment of Locally Advanced or Metastatic Solid Tumors

2021 ◽  
pp. 109158182199894
Author(s):  
Brian T. Welsh ◽  
Ryan Faucette ◽  
Sanela Bilic ◽  
Constance J. Martin ◽  
Thomas Schürpf ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Checkpoint Inhibitors ◽  
Human Peripheral Blood ◽  
Phase 1 ◽  
Locally Advanced ◽  
Acquired Resistance ◽  
Transforming Growth Factor Β ◽  
Human Antibody ◽  
Primary Resistance

Checkpoint inhibitors offer a promising immunotherapy strategy for cancer treatment; however, due to primary or acquired resistance, many patients do not achieve lasting clinical responses. Recently, the transforming growth factor-β (TGFβ) signaling pathway has been identified as a potential target to overcome primary resistance, although the nonselective inhibition of multiple TGFβ isoforms has led to dose-limiting cardiotoxicities. SRK-181 is a high-affinity, fully human antibody that selectively binds to latent TGFβ1 and inhibits its activation. To support SRK-181 clinical development, we present here a comprehensive preclinical assessment of its pharmacology, pharmacokinetics, and safety across multiple species. In vitro studies showed that SRK-181 has no effect on human platelet function and does not induce cytokine release in human peripheral blood. Four-week toxicology studies with SRK-181 showed that weekly intravenous administration achieved sustained serum exposure and was well tolerated in rats and monkeys, with no treatment-related adverse findings. The no-observed-adverse-effect levels levels were 200 mg/kg in rats and 300 mg/kg in monkeys, the highest doses tested, and provide a nonclinical safety factor of up to 813-fold (based on Cmax) above the phase 1 starting dose of 80 mg every 3 weeks. In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that SRK-181 is a selective inhibitor of latent TGFβ1 that does not produce the nonclinical toxicities associated with nonselective TGFβ inhibition. These data support the initiation and safe conduct of a phase 1 trial with SRK-181 in patients with advanced cancer.

scholarly journals Microfluidic tumor-on-a-chip model to evaluate the role of tumor environmental stress on NK cell exhaustion

2021 ◽  
Vol 7 (8) ◽  
pp. eabc2331 ◽  
Author(s):  
Jose M. Ayuso ◽  
Shujah Rehman ◽  
Maria Virumbrales-Munoz ◽  
Patrick H. McMinn ◽  
Peter Geiger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Waste Product ◽  
Extended Period ◽  
Cell Exhaustion

Solid tumors generate a suppressive environment that imposes an overwhelming burden on the immune system. Nutrient depletion, waste product accumulation, hypoxia, and pH acidification severely compromise the capacity of effector immune cells such as T and natural killer (NK) cells to destroy cancer cells. However, the specific molecular mechanisms driving immune suppression, as well as the capacity of immune cells to adapt to the suppressive environment, are not completely understood. Thus, here, we used an in vitro microfluidic tumor-on-a-chip platform to evaluate how NK cells respond to the tumor-induced suppressive environment. The results demonstrated that the suppressive environment created by the tumor gradually eroded NK cell cytotoxic capacity, leading to compromised NK cell surveillance and tumor tolerance. Further, NK cell exhaustion persisted for an extended period of time after removing NK cells from the microfluidic platform. Last, the addition of checkpoint inhibitors and immunomodulatory agents alleviated NK cell exhaustion.

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