Key Points
Anti-OX40 treatment does not impair TIL Treg suppressive function.
OX40 ligation enhances Treg and Tconv proliferation through Tconv cell IL-2 secretion.
TIL Tregs proliferate and produce Th1 cytokines after anti-OX40 treatment.
Abstract
OX40 is a costimulatory molecule from the TNFR family. In mice, it is expressed on Foxp3+ regulatory T cells (Tregs) constitutively and on conventional CD4 (Tconv) and CD8 T cells after Ag encounter. OX40 agonists are in clinical development to enhance antitumor immune responses, and one proposed mechanism of action is loss of Treg suppressive function. Studies have postulated that agonist OX40 therapy can impair Treg suppressive function. Using tools developed since the initial studies were published, we evaluated a direct effect of OX40 agonism on Treg function. We conclude that OX40 agonist Abs do not intrinsically impair Treg function but rather enhance Tconv cell IL-2 production, increasing Treg and Tconv cell proliferation. OX40-stimulated Tregs retain suppressive function, but also gain IFN-γ, TNF-α, and granzyme B expression. These data help resolve mechanistic questions regarding OX40 agonist immunotherapy and thus are relevant to developing combination therapies that target distinct T cell functions.
Footnotes
This work was supported in part by American Cancer Society Postdoctoral Fellow Grant PF-14-053-01 and National Institutes of Health Grant T32AI078903, and an OHSU Foundation grant (to A.E.M.). A.D.W. was funded by National Institutes of Health Grant 5R01CA102577, a sponsored research agreement with MedImmune, and the Providence Medical Foundation. S.E.M. is supported by the Medical Research Foundation of Oregon and a grant from the M.J. Murdock Charitable Trust (NS-201812034).
The online version of this article contains supplemental material.
- Received June 24, 2019.
- Accepted July 22, 2019.
- Copyright © 2019 by The American Association of Immunologists, Inc.