Abstract 15833: Immune Checkpoint Inhibitor Myocarditis Subtypes are Determined by a Cd8-dependent Transcriptional Program

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Daniel Finke ◽  
Markus B Heckmann ◽  
Janek Salatzki ◽  
Johannes Riffel ◽  
Esther Herpel ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Clinical Analysis ◽  
Cardiac Biomarkers ◽  
University Hospitals ◽  
Dilatative Cardiomyopathy ◽  
Transcriptional Changes ◽  
Upregulated Genes

Introduction: Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing clinical use leads to higher rates of adverse immune related events (irAEs). One of those irAEs is the ICI-induced myocarditis (ICIM) - a rare phenomenon with an estimated mortality rate of up to 50%. We aimed to characterize the molecular changes of ICIM which are not yet understood completely. Methods: Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n=9) with samples from dilatative cardiomyopathy (DCM, n=11) and virus-induced myocarditis (VIM, n=5). Results: Clinical analysis of 19 patients with ICIM showed an inconsistent presentation, e.g. an elevation of cardiac biomarkers (hsTnT, NT-proBNP, CK), a drop in leftventricular ejection fraction or late gadolinium enhancement in cMRI. We found 3784 (FDR <0.05) upregulated genes in ICIM. Among the genes that were related to antigen presentation and processing, we mainly found an upregulation of CD8. CD8-dependent clustering of ICI-patients, on the other hand, was associated with a number of immune cell-specific genes (compared to VIM: CXCL11 (log2 fc 3.24), CXCL9 (log2 fc 4.37), GBP6 (log2 fc 5.37), GBP5 (log2 fc 3.21). Analysis of high- and low-expressing CD8 positive biopsies identified two expression patterns, suggesting different pathological mechanisms for ICIM. Conclusion: Taken together, we were able to identify CD8 and CD8-associated genes as specifically regulated transcripts in ICIM. Moreover, based on the variable clinical phenotype, we propose that analysis of CD8 and CD8-dependent genes will be important to identify ICIM patients and to potentially sub-differentiate different phenotypes.

scholarly journals Immune-checkpoint engagement as predictive biomarkers in clear cell renal cell carcinoma and melanoma

2020 ◽  
Author(s):  
Lissete Sánchez-Magraner ◽  
James Miles ◽  
Claire Baker ◽  
Christopher J Applebee ◽  
Dae-Jin Lee ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Predictive Biomarkers ◽  
Immune Checkpoints ◽  
Ligand Interaction ◽  
Receptor Ligand ◽  
Programmed Death ◽  
Cell Cell

ABSTRACTMany cancers are termed immuno-evasive due to expression of immuno-modulatory ligands. Programmed death ligand-1 (PD-L1) and cluster of differentiation 80/86 (CD80/86) interact with their receptors, programmed death receptor-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4), on tumour infiltrating leukocytes, thus eliciting immunosuppression. Immunotherapies aimed at blocking these interactions are revolutionising cancer treatments, albeit in an inadequately described patient subset.Our prognostic assay, utilising amplified two-site time-resolved Förster resonance energy transfer (iFRET), quantifies PD-1/ PD-L1 and CTLA-4/ CD80 cell-cell interactions in single cell assays and tumour biopsies. iFRET efficiencies demonstrate, in cell-cell engagement models, that receptor-ligand interactions are significantly lower with anti-PD-1 or anti-CTLA-4 blocking antibodies. In patient samples, iFRET detects immune-cell/tumour-cell interaction variance in different cancers. These results revealed inter-cancer, inter-patient and intra-tumoural heterogeneity of engaged immune-checkpoints, contradicting their ligand expression patterns. Exploiting spatio-temporal interactions of immune-checkpoint proteins defined biomarker functionality for determining whether checkpoint inhibitors are appropriate treatments.Statement of SignificanceQuantitative photophysics exploitation in determining immune-checkpoint engagement, as predictive biomarkers in cancers led to revealing inter-cancer, inter-patient and intra-tumoural heterogeneity of the engaged immune-checkpoints. This receptor-ligand interaction did not reflect simple expression patterns of these immuno-modulatory proteins. Our findings may affect immunotherapies aimed at blocking these intercellular interactions in patients.

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 Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS

2018 ◽  
Vol 2 (17) ◽  
pp. 2242-2252 ◽  
Author(s):  
Takeshi Sugio ◽  
Kohta Miyawaki ◽  
Koji Kato ◽  
Kensuke Sasaki ◽  
Kyohei Yamada ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Therapeutic Options ◽  
Patient Subgroup ◽  
Key Points ◽  
Disease Subtypes

Key Points Microenvironmental immune cell signatures stratify PTCL-NOS patients into clinically meaningful disease subtypes. Immune-checkpoint inhibitors represent potential therapeutic options for a PTCL-NOS patient subgroup.

scholarly journals Combinatorial immunotherapies overcome MYC-driven immune evasion

2021 ◽  
Author(s):  
Joyce V. Lee ◽  
Filomena Houseley ◽  
Christina Yau ◽  
Daniel Van de Mark ◽  
Rachel Nakagawa ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Mhc I ◽  
Number Of Patients ◽  
Tumor Outgrowth

For many human cancers, including triple negative breast cancer (TNBC), a modest number of patients benefit from immune checkpoint inhibitors, and few experience cancer remission. Expression of programed death-ligand 1 (PD-L1), tumor immune infiltration, or tumor mutation burden have been widely investigated for predicting cancer immunotherapy response. Whether specific oncogenes diminish response to immunotherapy and whether these effects are reversible remains poorly understood. We predicted that MYC, an oncogene that is frequently overexpressed and is associated with worse prognosis, may predict immunotherapy response in patients with TNBC. Here, we report that MYC-elevated TNBCs are resistant to immune checkpoint inhibitors. Using mouse models of TNBC and patient data we report that MYC signaling is associated with low tumor cell PD-L1, low overall immune cell infiltration, and low tumor cell MHC-I expression. Restoring interferon signaling in the tumor reduces MYC expression and increases MHC-I expression. By combining a TLR9 agonist and an agonistic antibody against OX40 with anti-PD-L1, most mice experience complete tumor regression and are protected from new TNBC tumor outgrowth. Our findings demonstrate that MYC-dependent immune evasion is reversible and druggable, and if strategically targeted, may improve outcomes for patients treated with immune checkpoint inhibitors.

scholarly journals Immunomodulating Therapies in Breast Cancer—From Prognosis to Clinical Practice

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4883
Author(s):  
Marcus Schmidt ◽  
Anne-Sophie Heimes
Keyword(s):  
Breast Cancer ◽  
Immune Responses ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Response To Chemotherapy ◽  
Infiltrating Lymphocytes

The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

scholarly journals Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jia-Wei Luo ◽  
Yan-Hua Guo ◽  
Feng-Ying Wu ◽  
Xue-Fei Li ◽  
Xue-Cheng Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Egfr Mutations ◽  
Wild Type ◽  
Egfr Mutant

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients ( P = 0.0065 ). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

Current status of treatment with immune checkpoint inhibitors in the field of gynecological oncology

2019 ◽  
pp. 1-2
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Cell ◽  
Clinical Medicine ◽  
Checkpoint Inhibitors ◽  
Cell System ◽  
Current Status ◽  
Living Body ◽  
Foreign Objects

In our living body, foreign objects are eliminated by the function of immunity. On the other hand, cancer cells are known to have a mechanism to break the immune cell system that is trying to attack cancer in order to escape from the attack of immune cells. “Immune checkpoint inhibitors” prevent cancer cells from breaking the immune system. Therefore, the “immune checkpoint inhibitor” is a drug that induces the immune function to attack the original cancer. Currently, PD-1 antibody, PD-L1 antibody and CTLA-4 antibody are used in clinical medicine as anti-cancer drugs. In this paper, the authors discuss the clinical use of immune checkpoint inhibitors in gynecological tumors.

Magnitude and duration of immune checkpoint up-regulation and changes in the immune microenvironment post chemo-radiation (CRT) in esophageal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4060-4060
Author(s):  
Ronan Joseph Kelly ◽  
Ali Hussainy Zaidi ◽  
Matthew A Smith ◽  
Ashten N Omstead ◽  
Juliann E Kosovec ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Qrt Pcr ◽  
Tumor Bearing ◽  
Post Radiation ◽  
The Impact

4060 Background: PD-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25%. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with CRT in earlier stage esophageal cancer may prevent metastatic disease in a greater proportion of patients. This study assessed the impact of CRT on the immune microenvironment and the expression patterns of multiple immune checkpoints to optimally design neoadjuvant clinical trials. Methods: To determine the effects of CRT on resected esophageal adenocarcinomas (EAC), we examined the immune microenvironment pre and post CRT using IHC, LCM followed by qRT-PCR, and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 sensitization, esophagojejunostomy were performed on rats to induce gastroduodenoesophageal reflux and EAC formation. First, tumor bearing animals were dosed with single fraction 13 Gy or 16 Gy radiation to determine safety, dose correlation, and PD-L1 sensitization using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual tumor bearing animals were determined using serial endoscopic biopsies at baseline, 1, 5 and 9 weeks post 16 Gy radiation. Results: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including – TIM3, GITR, IDO1, LAG3, CD137, OX40 and KIR. The animal model results indicated PD-L1 upregulation is dose dependent and transiently elevated post radiation exposure. Conclusions: Collectively, these findings provide insights into the evolving immune landscape after CRT and have significant implications for future neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. Currently, we are conducting a neoadjuvant trial assessing Nivolumab or Nivolumab/Ipilimumab in combination with CRT in stage II/III operable esophageal cancer.

Analysis of Toxicity Profile and Predictors of Immune Checkpoint Inhibitor-Related Adverse Events

2020 ◽  
Author(s):  
Rilan Bai ◽  
Naifei Chen ◽  
Xiao Chen ◽  
Lingyu Li ◽  
Wei Song ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Area Under The Curve ◽  
Progression Free Survival ◽  
Toxicity Profile ◽  
Baseline Characteristics ◽  
Pan Cancer

Abstract Background and objectiveIn recent years, a wide variety of immune checkpoint inhibitors (ICIs) is emerging and has shown long-lasting and significant efficacy in the treatment of various malignant tumors. However, about 10% of patients experience serious and even life-threatening immune-related adverse events (irAEs). Fully understanding the characteristics of toxic effects and biomarkers to predict irAEs is, therefore, of great interest. We aimed to retrospectively analyze the toxicity profile and predictors of irAEs, as well as the correlation between irAEs and clinical efficacy in patients with advanced pan-cancer who were treated with multi-type ICIs in real-world.MethodsWe retrospectively analyzed data from 105 patients with advanced pan-cancer who were treated with multi-type ICIs in the First Hospital of Jilin University from Jan 1, 2016 to Aug 1, 2020. We used logistic regression analyses to investigate associations between irAEs and clinical baseline characteristics, blood count parameters, and biochemical indicators during the treatment. Receiver-operating characteristic (ROC) curve was used to determine a cutoff value for parameters and area under the curve (AUC). Kaplan–Meier and cox multivariate regression analysis were performed to estimate the relationship of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS).ResultsWe found that lower relative lymphocyte count (RLC) (cutoff=0.285*10^9/L), higher albumin (ALB) (cutoff=39.05g/L) and higher absolute eosinophil count (AEC) (cutoff=0.175*10^9/L) were significantly associated with the occurrence of any irAEs, of which a higher AEC (cutoff=0.205*10^9/L) was strongly associated with skin-related irAEs (HR=0.163, p=0.004); And a higher lactate dehydrogenase (LDH) level (cutoff=237.5U/L) was an independent predictor of serious irAEs (HR=0.199, p=0.022). In the analysis of immune cell subgroup, lower absolute CD8+CD28- T cell count (HR=0.806; 95%CI: 0.643-1.011; p=0.062), a regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant; And a higher percentage of CD19+ B cells were associated with the occurrence of serious irAEs and irAEs of grade ≥2 (p＜0.05). In addition, our study showed that patients with any grade irAE had a significantly better PFS (8.37 vs.3.77 months, HR=2.02, p=0.0038) and OS (24.77 vs.13.83 months, HR=1.78, p=0.029).ConclusionsThis retrospective study reported the clinical profile data of irAEs of unselected patients in the real world, and explored some parameters that may all be conventional, potentially predictable markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may contribute to fully assess the risk-benefit ratio for patients treated with ICIs.

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