Thymosin α1 protects from CTLA-4 intestinal immunopathology
Giorgia Renga1, Marina M Bellet1, Marilena Pariano1
1Department of Experimental Medicine, University of Perugia, Perugia, Italy.
Abstract:
The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor-induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1-dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.
Insights
Thymosin α1 (Tα1) protects against immune checkpoint inhibitor-induced colitis by promoting a tolerogenic pathway. It also modulates T-cell subsets in tumors, potentially improving cancer therapy safety and efficacy.
Area of Science:
- Immunology
- Cancer Therapy
- Drug Safety
Background:
- Immune checkpoint inhibitors (ICIs) are effective cancer treatments but can cause autoimmune-like side effects.
- Ensuring the safety of ICIs is crucial for their broader clinical application.
- Understanding mechanisms to mitigate ICI-induced toxicity is a key research area.
Purpose of the Study:
- To investigate the potential of thymosin α1 (Tα1) in preventing immune-related adverse events associated with ICIs.
- To elucidate the mechanisms by which Tα1 exerts its protective effects in a model of ICI-induced colitis.
- To evaluate Tα1's impact on the tumor microenvironment and its potential to enhance ICI efficacy.
Main Methods:
- Utilized a murine model of immune checkpoint inhibitor-induced colitis.
- Administered thymosin α1 (Tα1) to assess its protective effects on intestinal toxicity.
- Analyzed immune cell populations, cytokine profiles, and gene expression in both the gut and tumor microenvironment.
- Investigated the role of indoleamine 2,3-dioxygenase 1 (IDO1) in Tα1-mediated protection.
Main Results:
- Tα1 significantly protected mice from intestinal toxicity in the colitis model.
- Tα1 promoted the indoleamine 2,3-dioxygenase 1 (IDO1)-dependent tolerogenic immune pathway in the gut.
- In the tumor microenvironment, Tα1 modulated T-cell infiltration by altering the CD8+/Treg cell ratio, without inducing IDO1.
Conclusions:
- Thymosin α1 (Tα1) demonstrates potential as a therapeutic agent to mitigate immune-related adverse events from ICIs.
- Tα1 employs distinct, context-dependent mechanisms to improve the safety and efficacy profile of cancer immunotherapies.
- Further research into Tα1 could lead to safer and more effective cancer treatment strategies.
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