Effect of gut microbiota on immune checkpoint inhibitor (ICI) based cancer immunotherapy

2021 ◽  
Vol 50 (4) ◽  
pp. 423
Author(s):  
A. Y. P. Perera ◽  
S. D. S. S. Sooriyapathirana ◽  
S. Rajapakse ◽  
J. A. M. S. Jayatilake
Keyword(s):  
Gut Microbiota ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor

scholarly journals Paraneoplastic Neurological Syndromes and Beyond Emerging With the Introduction of Immune Checkpoint Inhibitor Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Cristina Valencia-Sanchez ◽  
Anastasia Zekeridou
Keyword(s):  
Nervous System ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Neurological Complications ◽  
High Dose ◽  
Paraneoplastic Neurological Syndromes ◽  
Clinical Presentations

Paraneoplastic neurological syndromes are more commonly seen with malignancies such as small cell lung cancer, thymoma, gynecological malignancies, and breast cancer as well as seminoma. With the introduction of immune checkpoint inhibitor (ICI) cancer immunotherapy we see an increase of autoimmune neurological complications in patients with malignancies not traditionally associated with paraneoplastic neurological syndromes, such as melanoma and renal cell carcinoma. Immune checkpoint inhibitors enhance antitumor immune responses resulting often in immune-related adverse effects that can affect any organ, including the central and peripheral nervous system, neuromuscular junction and muscle. Neurological complications are rare; neuromuscular complications are more common than central nervous system ones but multifocal neurological presentations are often encountered. The vast majority of neurological complications appear within 3 months of ICI initiation, but have been described even after ICI cessation. Neural autoantibody testing reveals autoantibodies in approximately half of the patients with CNS complications. Early suspicion and diagnosis is critical to avoid worsening and improve outcomes. Therapeutic strategies depend on the severity of the symptoms and initially typically involve discontinuation of ICI and high dose steroids. Further immunosuppression might be necessary. Outcomes are dependent on patient's characteristics and clinical presentations.

scholarly journals NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020

2020 ◽  
Vol 18 (3) ◽  
pp. 230-241 ◽  
Author(s):  
John A. Thompson ◽  
Bryan J. Schneider ◽  
Julie Brahmer ◽  
Stephanie Andrews ◽  
Philippe Armand ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Nccn Guidelines

The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.

scholarly journals Prevotellaceae produces butyrate to alleviate PD-1/PD-L1 inhibitor-related cardiotoxicity via PPARα-CYP4X1 axis in colonic macrophages

2022 ◽  
Vol 41 (1) ◽  
Author(s):  
Yaxin Chen ◽  
Yanzhuo Liu ◽  
Yang Wang ◽  
Xuewei Chen ◽  
Chenlong Wang ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Gut Microbiota ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Intestinal Barrier ◽  
Cardiomyocyte Apoptosis ◽  
Tnf Α ◽  
Gut Microbiota Dysbiosis ◽  
Proinflammatory Factors

Abstract Background Immune checkpoint inhibitor-related cardiotoxicity is one of the most lethal adverse effects, and thus, the identification of underlying mechanisms for developing strategies to overcome it has clinical importance. This study aimed to investigate whether microbiota-host interactions contribute to PD-1/PD-L1 inhibitor-related cardiotoxicity. Methods A mouse model of immune checkpoint inhibitor-related cardiotoxicity was constructed by PD-1/PD-L1 inhibitor BMS-1 (5 and 10 mg/kg), and cardiomyocyte apoptosis and cardiotoxicity were determined by hematoxylin and eosin, Masson’s trichome and TUNEL assays. 16S rRNA sequencing was used to define the gut microbiota composition. Gut microbiota metabolites short-chain fatty acids (SCFAs) were determined by HPLC. The serum levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB and lactate dehydrogenase) and the production of M1 factors (TNF-α and IL-1β) were measured by ELISA. The colonic macrophage phenotype was measured by mmunofluorescence and qPCR. The expression of Claudin-1, Occludin, ZO-1 and p-p65 was measured by western blot. The gene expression of peroxisome proliferator-activated receptor α (PPARα) and cytochrome P450 (CYP) 4X1 was determined using qPCR. Statistical analyses were performed using Student’s t-test for two-group comparisons, and one-way ANOVA followed by Student–Newman–Keul test for multiple-group comparisons. Results We observed intestinal barrier injury and gut microbiota dysbiosis characterized by Prevotellaceae and Rikenellaceae genus depletion and Escherichia-Shigella and Ruminococcaceae genus enrichment, accompanied by low butyrate production and M1-like polarization of colonic macrophages in BMS-1 (5 and 10 mg/kg)-induced cardiotoxicity. Fecal microbiota transplantation mirrored the effect of BMS-1 on cardiomyocyte apoptosis and cardiotoxicity, while macrophage depletion and neutralization of TNF-α and IL-1β greatly attenuated BMS-1-induced cardiotoxicity. Importantly, Prevotella loescheii recolonization and butyrate supplementation alleviated PD-1/PD-L1 inhibitor-related cardiotoxicity. Mechanistically, gut microbiota dysbiosis promoted M1-like polarization of colonic macrophages and the production of proinflammatory factors TNF-α and IL-1β through downregulation of PPARα-CYP4X1 axis. Conclusions Intestinal barrier dysfunction amplifies PD-1/PD-L1 inhibitor-related cardiotoxicity by upregulating proinflammatory factors TNF-α and IL-1β in colonic macrophages via downregulation of butyrate-PPARα-CYP4X1 axis. Thus, targeting gut microbiota to polarize colonic macrophages away from the M1-like phenotype could provide a potential therapeutic strategy for PD-1/PD-L1 inhibitor-related cardiotoxicity. Graphical abstract

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