Thymosin α1 protects from CTLA-4 intestinal immunopathology

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.

Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite

“…In both DSS colitis and tumor models, 3-IAld was administered every other day at a dose of 18 mg/kg, starting 4 days before DSS treatment or in concomitance with tumor challenge, as already described. 28 Models of immune-mediated colitis NSG mice 8-10 weeks old were injected intraperitoneally with 10 7 human peripheral blood mononuclear cells (PBMCs). Human blood samples were obtained from healthy donors, and fresh PBMCs were isolated by density-gradient separation (Ficoll Paque Plus, GE Open access Healthcare).…”

The Right Immune-Modulation at the Right Time: Thymosin α1 for Prevention of Severe COVID-19 in Cancer Patients

“…The favorable combination of thymosin α1 with an anti-PD-1 antibody has been already postulated in an experimental setting in which low doses of thymosin α1, while being ineffective alone, increased the efficacy of an anti-PD-1 antibody in the lung metastasis melanoma model [ 19 ]. Moreover, several evidence converge in the suggestion that thymosin α1 represents a plausible candidate to improve the safety and the efficacy profile of ICI [ 20 ], and, in particular, a preclinical study has shown the protective role of thymosin α1 from intestinal toxicity in a murine model of ICI-induced colitis [ 21 ].…”

Covid-19-Associated Pulmonary Aspergillosis: The Other Side of the Coin

“…Another example is represented by thymosin α1, an endogenous thymic peptide with a wide range of immunomodulatory activities [ 66 ] and the capacity to balance a dysregulated immune response in a context-dependent manner. Indeed, thymosin α1 could either be immunostimulatory, such as in cancer and immune deficiency, or promote tolerance in inflammatory conditions, for instance by inducing the indoleamine 2,3-dioxygenase 1 pathway [ 67 , 68 , 69 ] or promoting autophagy [ 68 ]. The latter process is increasingly being recognized as a regulator of lung health and protection against microbial infection, with potential relevance for a variety of lung diseases, including COVID-19 [ 70 ].…”