Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted
Young H Kim1, Su M Shin2, Beom K Choi3
1Biomedicine Production Branch, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
Journal of Immunology (Baltimore, Md. : 1950)
|October 2, 2015
Summary
Glucocorticoid-induced TNFR-related protein (GITR) signaling has dual effects. While it enhances effector T cell proliferation, it also promotes regulatory T cell (Treg) growth, potentially hindering anti-tumor immunity.
Area of Science:
- Immunology
- Cancer Biology
- T cell biology
Background:
- Glucocorticoid-induced TNFR-related protein (GITR) is expressed on effector and regulatory T cells (Tregs).
- Previous studies using anti-GITR monoclonal antibodies (mAbs) showed enhanced immune responses, but GITR-deficient T cells exhibit unexplained increased proliferation.
- The Fc region of mAbs can influence their activity, necessitating investigation of GITR signaling via its natural ligand.
Purpose of the Study:
- To compare the effects of GITR ligation using a pentamerized GITRL (pGITRL) with anti-GITR mAb on T cell responses.
- To elucidate the distinct roles of GITR signaling in effector and regulatory T cell function.
- To understand the impact of GITR signaling on anti-tumor immunity in the context of Treg cell accumulation.
Main Methods:
- Generation of a pentamerized GITRL (pGITRL) to ligate GITR.
- In vitro and in vivo assessment of T cell proliferation and immune responses.
- Evaluation of tumor growth suppression in MC38 adenocarcinoma models.
- Analysis of Treg cell populations within tumor tissue and draining lymph nodes.
- Comparison of pGITRL effects with anti-GITR mAb.
- Assessment of anti-tumor effects following CD4+ cell depletion.
Main Results:
- pGITRL enhanced effector and regulatory T cell proliferation more effectively than anti-GITR mAb in vitro and in vivo.
- pGITRL initially suppressed MC38 adenocarcinoma growth, but this effect was transient compared to the sustained suppression by anti-GITR mAb.
- pGITRL induced significant proliferation and accumulation of activated Foxp3(+)CD4(+) Treg cells in tumors and lymph nodes.
- Depletion of CD4+ cells markedly enhanced the anti-tumor effects of pGITRL.
- GITR signaling demonstrated stimulatory effects on effector T cells but inhibitory effects mediated through Treg cells.
Conclusions:
- GITR signaling has a complex role, stimulating effector T cells while promoting Treg cell expansion.
- The accumulation of activated Treg cells induced by pGITRL can counteract its adjuvant effect on anti-tumor immunity.
- Targeting GITR may require strategies to manage Treg cell-mediated suppression for optimal anti-cancer therapeutic outcomes.
