Gene expression profiling of lichenoid dermatitis immune‐related adverse event from immune checkpoint inhibitors reveals increased CD14 + and CD16 + monocytes driving an innate immune response

2019 ◽  
Vol 46 (9) ◽  
pp. 627-636 ◽  
Author(s):  
Jonathan L. Curry ◽  
Alexandre Reuben ◽  
Robert Szczepaniak‐Sloane ◽  
Jing Ning ◽  
Denái R. Milton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Adverse Event ◽  
Gene Expression Profiling ◽  
Innate Immune Response ◽  
Immune Checkpoint ◽  
Expression Profiling ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Innate Immune

scholarly journals Merkel cell polyomavirus infection induces an antiviral innate immune response in human dermal fibroblasts

2021 ◽  
Author(s):  
Nathan A. Krump ◽  
Ranran Wang ◽  
Wei Liu ◽  
June F. Yang ◽  
Tongcui Ma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immune Response ◽  
Immune Checkpoint ◽  
Dermal Fibroblasts ◽  
Merkel Cell Polyomavirus ◽  
Innate Immune ◽  
Human Dermal Fibroblasts ◽  
Merkel Cell ◽  
Infectious Cycle

Merkel cell polyomavirus (MCPyV) infects most of the human population asymptomatically, but in rare cases leads to a highly aggressive skin cancer called Merkel cell carcinoma (MCC). MCC incidence is much higher in aging and immunocompromised populations. The epidemiology of MCC suggests that dysbiosis between the host immune response and the MCPyV infectious cycle could contribute to the development of MCPyV-associated MCC. Insufficient restriction of MCPyV by normal cellular processes, for example, could promote the incidental oncogenic MCPyV integration events and/or entry into the original cell of MCC. Progress towards understanding MCPyV biology has been hindered by its narrow cellular tropism. Our discovery that primary human dermal fibroblasts (HDFs) support MCPyV infection has made it possible to closely model cellular responses to different stages of the infectious cycle. The present study reveals that the onset of MCPyV replication and early gene expression induces an inflammatory cytokine and interferon stimulated gene (ISG) response. The cGAS-STING pathway, in coordination with NF-κB, mediates induction of this innate immune gene expression program. Further, silencing of cGAS or NF-κB pathway factors led to elevated MCPyV replication. We also discovered that the PYHIN protein IFI16 localizes to MCPyV replication centers, but does not contribute to the induction of ISGs. Instead, IFI16 upregulates inflammatory cytokines in response to MCPyV infection by an alternative mechanism. The work described herein establishes a foundation for exploring how changes to the skin microenvironment induced by aging or immunodeficiency might alter the fate of MCPyV and its host cell to encourage carcinogenesis. Importance MCC has a high rate of mortality and an increasing incidence. Immune-checkpoint therapies have improved the prognosis of patients with metastatic MCC. Still, a significant proportion of the patients fail to respond to immune-checkpoint therapies or have a medical need for iatrogenic immune-suppression. A greater understanding of MCPyV biology could inform targeted therapies for MCPyV-associated MCC. Moreover, cellular events preceding MCC oncogenesis remain largely unknown. The present study aims to explore how MCPyV interfaces with innate immunity during its infectious cycle. We describe how MCPyV replication and/or transcription elicit an innate immune response via cGAS-STING, NF-κB, and IFI16. We also explore the impacts of this response on MCPyV replication. Our findings illustrate how healthy cellular conditions may allow low-level infection that evades immune destruction until highly active replication is restricted by host responses. Conversely, pathologic conditions could result in unbridled MCPyV replication that licenses MCC tumorigenesis.

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

Myocarditis as a rare, yet serious adverse event associated with immune checkpoint inhibitors in patients with non-small cell lung cancer: Case series from a large community-based cancer center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21047-e21047
Author(s):  
Mohamed Hendawi ◽  
Luke Peterson ◽  
Eyob ale Tadesse ◽  
Frank M. Wolf ◽  
Thomas D. Brown ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Event ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Serious Adverse Event

e21047 Background: Patients (pts) with lung cancer and other cancers treated with immune checkpoint inhibitors (ICI) may experience immune related adverse events (irAE). These can present with variable severity and with single- or multi-organ involvement including pneumonitis, colitis, hepatitis, and myocarditis/pericarditis. The incidence of myocarditis has been reported between 0.06% and 2.4% and is associated with a high mortality (25% to 50%). This retrospective review of real-world data (RWD) investigates myocarditis as a high-grade adverse event in pts with lung cancer treated with ICIs. Methods: Pts were identified and characterized using RWD in the Syapse Learning Health Network platform from 2010 to 2020 at Advocate Aurora Health Care. Eligible pts included: ≥18 years old; histologically confirmed NSCLC; and myocarditis diagnosis by ICD codes. Additional chart review was performed to confirm timing of ICI treatment and myocarditis. All pts identification and review were performed after IRB review. Results: 12,686 pts with non-small cell lung cancer were eligible for review. The median age at diagnosis was 70; 54% were female; 86% were White and 12% were Black; 1,975 (15.6%) were treated with an ICI and of those 4 cases (0.2%) of myocarditis were identified. All 4 pts were White females, ages 46, 59, 65, and 74 years. Pathology included lung adenocarcinoma (3) and an undifferentiated lung carcinoma (1). All pts had metastatic disease, and none had a prior history of cardiac disease. ICIs were pembrolizumab (2), durvalumab (1), and nivolumab (1). Median time from initial dose of ICI to diagnosis of myocarditis was 62 days [range: 42-185]. All 4 pts presented with chest pain and elevated troponin T [median 0.07 ng/ml (range: 0.06-0.08)]. All pts had echocardiography at the time of diagnosis, and 2 pts had cardiac MRI that confirmed myocarditis. 3 pts were treated with a prednisone taper. 1 pt died of recurrent congestive heart failure and ventricular tachycardia despite rescue attempt with high dose corticosteroids. 2 pts had additional concomitant irAEs of hypothyroidism/colitis, and thyroiditis/pneumonitis, respectively. Conclusions: Many irAEs are reversible. This RWD analysis confirms that clinically evident myocarditis is a rare but serious adverse event of ICI therapy. Early consideration, diagnosis, and intervention may help prevent poor outcomes. Termination of ICI therapy along with initiation of corticosteroids constitute the current standard of management. Further research is warranted to better identify high risk groups, surveillance measures, and improved management of ICI associated myocarditis.

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