Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy

Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism underlying irAEs remains to be fully elucidated, and the availability of predictive biomarkers is limited. Herein, we performed data mining by combining pharmacovigilance data and pan-cancer transcriptomic information to illustrate the relationships between alternative splicing characteristics and irAE risk of ICIs. Four distinct classes of splicing characteristics considered were associated with splicing factors, neoantigens, splicing isoforms, and splicing levels. Correlation analysis confirmed that expression levels of splicing factors were predictive of irAE risk. Adding DHX16 expression to the bivariate PD-L1 protein expression-fPD1 model markedly enhanced the prediction for irAE. Furthermore, we identified 668 and 1,131 potential predictors based on the correlation of the incidence of irAEs with splicing frequency and isoform expression, respectively. The functional analysis revealed that alternative splicing might contribute to irAE pathogenesis via coordinating innate and adaptive immunity. Remarkably, autoimmune-related genes and autoantigens were preferentially over-represented in these predictors for irAE, suggesting a close link between autoimmunity and irAE occurrence. In addition, we established a trivariate model composed of CDC42EP3-206, TMEM138-211, and IRX3-202, that could better predict the risk of irAE across various cancer types, indicating a potential application as promising biomarkers for irAE. Our study not only highlights the clinical relevance of alternative splicing for irAE development during checkpoint immunotherapy but also sheds new light on the mechanisms underlying irAEs.

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Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia

Future Oncology ◽

10.2217/fon-2020-0703 ◽

2020 ◽

Author(s):

Guanghui Xu ◽

Yuhao Wang ◽

Hushan Zhang ◽

Xueke She ◽

Jianjun Yang

Keyword(s):

Current Knowledge ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

The Body ◽

Low Grade ◽

Ablative Therapies ◽

Cancer Types ◽

New Treatment ◽

Well Differentiated

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.

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Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

Cancers ◽

10.3390/cancers13050989 ◽

2021 ◽

Vol 13 (5) ◽

pp. 989

Author(s):

Heidar J. Albandar ◽

Jacob Fuqua ◽

Jasim M. Albandar ◽

Salahuddin Safi ◽

Samuel A. Merrill ◽

...

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Survival Outcomes ◽

Limited Data ◽

Risk Of Death ◽

Survival Difference ◽

Histopathologic Diagnosis ◽

Cancer Types

Introduction: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. Methods: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011–2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. Results: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. Conclusions: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

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MBNL1 alternative splicing isoforms play opposing roles in cancer

Life Science Alliance ◽

10.26508/lsa.201800157 ◽

2018 ◽

Vol 1 (5) ◽

pp. e201800157 ◽

Cited By ~ 20

Author(s):

Tommaso Tabaglio ◽

Diana HP Low ◽

Winnie Koon Lay Teo ◽

Pierre Alexis Goy ◽

Piotr Cywoniuk ◽

...

Keyword(s):

Alternative Splicing ◽

Cancer Cells ◽

Cancer Progression ◽

Gene Function ◽

Dominant Negative ◽

Individual Gene ◽

Cancer Types ◽

Splicing Isoforms ◽

Isoform Switching ◽

And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

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Biomarkers for Predicting Response to Immunotherapy with Immune Checkpoint Inhibitors in Cancer Patients

Clinical Chemistry ◽

10.1373/clinchem.2019.303644 ◽

2019 ◽

Vol 65 (10) ◽

pp. 1228-1238 ◽

Cited By ~ 23

Author(s):

Michael J Duffy ◽

John Crown

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Predictive Biomarkers ◽

Future Research ◽

Specific Gene ◽

Tumor Type ◽

Clinical Use ◽

Durable Response ◽

Cancer Types

Abstract BACKGROUND Immunotherapy, especially the use of immune checkpoint inhibitors, has revolutionized the management of several different cancer types in recent years. However, for most types of cancer, only a minority of patients experience a durable response. Furthermore, administration of immunotherapy can result in serious adverse reactions. Thus, for the most efficient and effective use of immunotherapy, accurate predictive biomarkers that have undergone analytical and clinical validation are necessary. CONTENT Among the most widely investigated predictive biomarkers for immunotherapy are programmed death-ligand 1 (PD-L1), microsatellite instability/defective mismatch repair (MSI/dMMR), and tumor mutational burden (TMB). MSI/dMMR is approved for clinical use irrespective of the tumor type, whereas PD-L1 is approved only for use in certain cancer types (e.g., for predicting response to first-line pembrolizumab monotherapy in non-small cell lung cancer). Although not yet approved for clinical use, TMB has been shown to predict response to several different forms of immunotherapy and across multiple cancer types. Less widely investigated predictive biomarkers for immunotherapy include tumor-infiltrating CD8+ lymphocytes and specific gene signatures. Despite being widely investigated, assays for MSI/dMMR, PD-L1, and TMB lack standardization and are still evolving. An urgent focus of future research should be the optimization and standardization of method for determining these biomarkers. SUMMARY Biomarkers for predicting response to immunotherapy are paving the way for personalized treatment for patients with diverse cancer types. However, standardization of the available biomarker assays is an urgent requirement.

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Strategies for improving the management of immune-related adverse events

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001754 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001754

Author(s):

Aung Naing ◽

Joud Hajjar ◽

James L Gulley ◽

Michael B Atkins ◽

Gennaro Ciliberto ◽

...

Keyword(s):

Side Effects ◽

Adverse Events ◽

Checkpoint Inhibitors ◽

Digital Health ◽

Immunosuppressive Agents ◽

Significant Proportion ◽

Cell Activity ◽

Predictive Biomarkers ◽

Chemotherapeutic Agents ◽

Diagnostic Tools

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient’s voice, and sharing evolving data to improve the management of irAEs.

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Biological bases of cancer immunotherapy

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2021.5 ◽

2021 ◽

Vol 23 ◽

Author(s):

Maryanne M. Gonzales Carazas ◽

Joseph A. Pinto ◽

Fanny L. Casado

Keyword(s):

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Historical Review ◽

Predictive Biomarkers ◽

High Variability ◽

Therapeutic Approaches ◽

Cancer Treatments ◽

Cancer Types

Abstract Immunotherapy has changed the landscape of cancer treatment and has significantly improved the outcome of several cancer types including breast, lung, colorectal and prostate. Neoantigen recognition and immune checkpoint inhibitors are nowadays the milestones of different immunotherapeutic regimes; however, high cost, primary and acquired resistance and the high variability of responses make their extensive use difficult. The development of better predictive biomarkers that represent tumour diversity shows promise because there is a significant body of clinical data showing a spectrum of immunotherapeutic responses that might be related back to their specific characteristics. This article makes a conceptual and historical review to summarise the main advances in our understanding of the role of the immune system in cancer, while describing the methodological details that have been successfully implemented on cancer treatments and that may hold the key to improved therapeutic approaches.

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Detect it so you can treat it: a case series and proposed checklist to detect neurotoxicity in checkpoint therapy

10.21203/rs.3.rs-19760/v1 ◽

2020 ◽

Author(s):

Saskia Bolz ◽

Thivyah Ramakrishnan ◽

Michael Fleischer ◽

Elisabeth Livingstone ◽

Benjamin Stolte ◽

...

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Case Series ◽

Transverse Myelitis ◽

University Hospital ◽

Life Threatening ◽

Checkpoint Inhibitor Therapy ◽

Cancer Types ◽

Brachial Plexus Neuritis

Abstract Background: Checkpoint inhibitors show impressive and durable responses in various cancer types and provide new avenues for cancer immunotherapy. However, these drugs have a variety of adverse events. Common autoimmune-related adverse effects include fatigue, hepatitis, skin rash, endocrine deficiencies, and colitis. Neurotoxicity has been reported, but its incidence and course remain unclear.Methods: To illustrate the broad spectrum of neurotoxicity, we exemplarily report the neurological adverse events of five patients with melanoma and one patient with differentiated thyroid cancer who received checkpoint inhibitors at Essen University Hospital (Essen, Germany).Results: After treatment with ipilimumab, nivolumab or pembrolizumab, neurotoxic effects included hypophysitis-associated neck pain and headache, Guillain-Barré syndrome, transverse myelitis, acute brachial plexus neuritis, and ocular myasthenia gravis.Conclusions: Checkpoint inhibitor therapy remains a success story; however, neurological immune-related adverse events may cause severe life-threatening conditions. We propose a checklist for the early detection of neurological adverse events during routine clinical treatment to prevent more severe courses of checkpoint inhibitor-induced neurotoxicity.

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Prognostic Implications of Pan-cancer CMTM6 Expression and Its Relationship With the Immune Microenvironment

10.21203/rs.3.rs-38154/v1 ◽

2020 ◽

Author(s):

Minghui Zhang ◽

Yanbin Zhao ◽

Haihong Pu ◽

Shengyue Guo ◽

Shuai Zhang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Protein Expression ◽

Cell Carcinoma ◽

Squamous Cell ◽

Prognostic Value ◽

Expression Data ◽

Immune Microenvironment ◽

Cancer Types ◽

L1 Protein ◽

Pan Cancer

Abstract Background: CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) reportedly stabilizes programmed death-ligand 1 (PD-L1) and enhances the efficacy of immunotherapy. However, correlations between CMTM6 expression and the immune microenvironment and its prognostic value remain unknown in a variety of tumors.Methods: CMTM6 expression data were obtained from The Cancer Genome Atlas (TCGA) for 33 cancer types classified into high and low expression subgroups according to the median CMTM6 expression value. Pan-cancer analysis of CMTM6 protein expression in 20 tumor types was performed using a cohort from the Human Protein Atlas (HPA). PD-L1 protein expression data were obtained from The Cancer Proteome Atlas (TCPA) for 32 cancer types. Frequencies of CMTM6 copy number alterations and mutations were analyzed using cBioPortal. MANTIS was employed to estimate microsatellite instability in the TCGA cohort. CIBERSORT and the ESTIMATE algorithm were applied to estimate the relative fractions of infiltrating immune cell types and immune scores, respectively. Kaplan–Meier survival curve analysis was performed to assess the pan-cancer prognostic value of CMTM6.Results: CMTM6 is heterogeneously expressed in diverse cancers. Further, the results revealed low CMTM6 mutation frequencies in multiple cancers. Among them, CMTM6 mutation frequency was the highest in uterine cancer. Additionally, CMTM6 expression was related to PD-L1 protein expression in breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, cholangiocarcinoma, glioblastoma multiforme (GBM), head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma, sarcoma (SARC), stomach adenocarcinoma, and uterine carcinosarcoma. Increased CMTM6 expression may be associated with increased infiltration of neutrophils in some types of cancer. Finally, pan-cancer analysis indicated that CMTM6 expression was closely related to overall survival in adrenocortical carcinoma, GBM, acute myeloid leukemia, liver hepatocellular carcinoma, mesothelioma, SARC, thymoma, and uveal melanoma. Conclusions: Taken together, these findings highlight that CMTM6 plays an important role in the tumor immune microenvironment, and CMTM6 has been identified to have prognostic value in some types of cancers.Thus, CMTM6 is a potential target for cancer immunotherapy and an effective prognostic biomarker.

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

10.21203/rs.3.rs-95117/v1 ◽

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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Imaging of Adverse Events Related to Checkpoint Inhibitor Therapy

Diagnostics ◽

10.3390/diagnostics10040216 ◽

2020 ◽

Vol 10 (4) ◽

pp. 216 ◽

Cited By ~ 2

Author(s):

Vanina Vani ◽

Daniele Regge ◽

Giovanni Cappello ◽

Michela Gabelloni ◽

Emanuele Neri

Keyword(s):

Adverse Events ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Appropriate Treatment ◽

Endocrine Organs ◽

Standard Of Practice ◽

Checkpoint Inhibitor Therapy ◽

Cancer Types ◽

Proper Diagnosis ◽

Improve Patient

Immunotherapy with checkpoint inhibitors (ICIs) is becoming standard of practice for an increasing number of cancer types. ICIs enhance T-cell action against the cancer cells. By unbalancing the immune system ICIs may cause dysimmune toxicities, a series of disorders broadly defined immune-related adverse events (irAEs). IrAEs may affect any organ or apparatus and most frequently involve skin, colon, endocrine organs, liver, and lungs. Early identification and appropriate treatment of irAEs can improve patient outcome. The paper aims at reviewing mechanisms of the occurrence of irAEs, the importance of a proper diagnosis and the main pillars of therapy. To provide effective guidance to the comprehension of major irAEs imaging findings will be reviewed.

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