Interruption of Thymic Activity in Adult Mice Improves Responses to Tumor Immunotherapy
- 1 March 2021
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 206 (5), 978-986
- https://doi.org/10.4049/jimmunol.2000626
Abstract
The thymus produces precursors of both conventional T cells (Tconv; also known as effector T cells) and regulatory T cells (Treg) whose interactions prevent autoimmunity while allowing efficient protective immune responses. Tumors express a composite of self-antigens and tumor-specific Ags and engage both Tconv and Treg. Along the aging process, the thymus involutes, and tumor prevalence increases, a correlation proposed previously to result from effector cell decline. In this work, we directly tested whether interruption of thymic activity in adult mice affects Foxp3-expressing Treg composition and function and alters tumor immune surveillance. Young adult mice, on two different genetic backgrounds, were surgically thymectomized (TxT) and analyzed or challenged 2 mo later. Cellular analysis revealed a 10-fold decrease in both Tconv and Treg numbers and a bias for activated cells. The persisting Treg displayed reduced stability of Foxp3 expression and, as a population, showed a compromised return to homeostasis upon induced perturbations. We next tested the growth of three tumor models from different tissue origins and/or presenting distinct degrees of spontaneous immunogenicity. In none of these conditions, adult TxT facilitated tumor growth. Rather, TxT enhanced the efficacy of antitumor immunotherapies targeting Treg and/or the immune checkpoint CTLA4, as evidenced by the increased frequency of responder mice and decreased intratumoral Treg to CD8+IFN-γ+ cell ratio. Together, our findings point to a scenario in which abrogation of thymic activities affects preferentially the regulatory over the ridding arm of the immune activities elicited by tumors and argues that higher prevalence of tumors with age cannot be solely attributed to thymic output decline.Keywords
Funding Information
- Instituto Gulbenkian de Ciência–Fundação Calouste Gulbenkian
- Fundação para a Ciência e a Tecnologia (SFRH/BD/52435/2013, UID/Multi/04555/2013)
- European Regional Development Fund (CONGENTO)
This publication has 40 references indexed in Scilit:
- Impact of aging on antigen presentation cell function of dendritic cellsCurrent Opinion in Immunology, 2013
- Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axisNature, 2013
- TIM3+FOXP3+regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancerOncoImmunology, 2013
- Regulatory T cells and Foxp3Immunological Reviews, 2011
- Cutting Edge: Intrathymic Differentiation of Adaptive Foxp3+ Regulatory T Cells upon Peripheral Proinflammatory ImmunizationThe Journal of Immunology, 2010
- Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cellsEuropean Journal of Immunology, 2009
- Steroid treatments in mice do not alter the number and function of regulatory T cells, but amplify cyclophosphamide-induced autoimmune diseaseJournal of Autoimmunity, 2009
- Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditionsEuropean Journal of Immunology, 2009
- Thymic output in aged miceProceedings of the National Academy of Sciences of the United States of America, 2006
- Continued maturation of thymic emigrants in the peripheryNature Immunology, 2004