journal contribution
posted on 2023-03-31, 00:30 authored by Jing Liu, Stephen J. Blake, Heidi Harjunpää, Kirsten A. Fairfax, Michelle C.R. Yong, Stacey Allen, Holbrook E. Kohrt, Kazuyoshi Takeda, Mark J. Smyth, Michele W.L. Teng Kinetics of Treg depletion in tumor-bearing Foxp3-DTR mice (S1); Development of blepharitis in tumor-bearing Foxp3-DTR mice after multiple DT treatment (S2); Prolonged Treg depletion induces severe irAEs in MC38 tumor-bearing mice (S3); Transient Treg depletion or multiple anti-CTLA-4 and anti-PD-1 treatment induce similar biochemical autoimmunity in tumor-bearing mice (S4); Transient Treg depletion of tumor-bearing mice increases the expression of PD-1, TIM-3 and CD137 on T cells from spleen but not tumor (S5); Transient Treg depletion in combination with anti-PD-1, anti-TIM-3 or anti-CD137 can all suppress established 4T1.2 or MC38 tumor growth (S6); Transient Treg depletion in combination with anti-PD-1, anti-TIM-3 or anti-CD137 differentially suppressed established CT26L5 tumor growth (S7); Transient Treg depletion in combination with anti-CD137 in tumor-bearing Foxp3-DTR mice induces severe irAEs (S8); Transient Treg depletion in combination with anti-CD137 increases the proportion of CD8+ T cells in multiple organs of tumor-bearing mice (S9); Transient Treg depletion in combination with anti-CD137 increases inflammatory cytokines in sera of tumor bearing mice (S10).
Funding
CDF1
National Health and Medical Research Council of Australia
CCQ
WEWC
NH&MRC
Susan Komen for the Cure
University of Queensland International Postgraduate Research
History
ARTICLE ABSTRACT
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137–treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288–301. ©2016 AACR.
