Related Experiment Video
Updated: Dec 26, 2025
Author Spotlight: Unveiling Transmembrane Protein Family-Related Markers in Gastric Cancer and Implications for Targeted Therapies
Published on: September 15, 2023
Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint
Csaba Kerepesi1,2, Tibor Bakacs3, Ralph W Moss4
1Institute for Computer Science and Control (SZTAKI), Kende u 13-17, Budapest, 1111, Hungary. kerepesi@sztaki.hu.
Abstract:
More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.
Insights
Immune checkpoint inhibitor (ICI) therapy can cause immune-related adverse events (irAEs) by unleashing T cells. A study found a correlation between irAEs and tumor mutational burden, suggesting T cells target both tumors and self-tissues.
Area of Science:
- Oncology
- Immunology
- Pharmacovigilance
Background:
- Cancer immunotherapy has revolutionized treatment, with over 2000 agents developed.
- Immune checkpoint inhibitors (ICIs) show promise but cause immune-related adverse events (irAEs) by affecting self-tissue tolerance.
- A proposed mechanism for irAEs is a graft-versus-malignancy effect, similar to graft-versus-host disease.
Purpose of the Study:
- To investigate the hypothesis that irAEs stem from a graft-versus-malignancy-like mechanism.
- To explore the relationship between irAEs and tumor mutational burden (TMB) in patients receiving ICI therapy.
Main Methods:
- Utilized post-marketing adverse event data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).
- Analyzed data from 7677 patients across 19 cancer types.
- Calculated the reporting odds ratio (ROR) for irAEs and correlated it with tumor mutational burden.
Main Results:
- A significant positive correlation was observed between the ROR of irAEs and TMB in patients undergoing ICI therapy.
- This correlation was consistent across 19 different cancer types.
- The findings suggest ICI drugs activate T cells against both tumor antigens and self-antigens.
Conclusions:
- The study supports the hypothesis that irAEs are linked to a graft-versus-malignancy-like effect.
- ICI therapy may activate T cells targeting "altered-self" and self-antigens, contributing to both efficacy and toxicity.
- This understanding could inform strategies to mitigate irAEs while maximizing therapeutic benefits in cancer immunotherapy.
Related Concept Videos
01:27Tumor Immunotherapy
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:25Mutagenicity and Carcinogenicity