Tumor Immunotherapy: The mechanism of action of anti-CTLA-4 antibodies requires FcgR-dependant TREG depletion
Ipilimumab is an anti-CTLA-4 antibody used to treat metastatic melanoma. It’s one of only two cancer immunotherapy drugs the FDA has approved so far. CTLA-4 is a negative regulatory molecule found on activated T cells and on regulatory T cells (TREGs).
CTLA-4 is related to CD28, a T cell co-stimulatory receptor. It suppresses T cell function in two ways. It competes with CD28 for binding to CD80 and CD86 on antigen-presenting cells, and it pulls inhibitory molecules into the TCR signaling complex.
Researchers had assumed Ipilimumab works by releasing anti-tumor effector T cells from CTLA-4 inhibition, or by limiting TREG activity in the tumor. Either way, this raises the ratio of effector T cells to TREGs within the tumor.
Two recent studies show Ipilimumab has an additional mechanism: FcgR-dependent depletion of TREGs inside the tumor.
How Fc Gamma Receptors Work
Fcg receptors are a family of receptors that bind immunoglobulin (IgG) and trigger either activating or inhibitory signals.
- Activating receptors carry cytoplasmic ITAM motifs. They drive the cell to perform antibody-dependent cell-mediated cytotoxicity (ADCC) and to phagocytose antibody-labeled target cells.
- FcgRIIB is the only inhibitory Fcg receptor in mice and humans. It carries an ITIM motif that dampens the cell’s response instead.
Humans and mice each have four classes of IgG, and each class binds Fcg receptors with different affinity. Researchers believe these differing affinities help explain why different antibodies against the same target can produce very different clinical results.
Ipilimumab Depletes Regulatory T Cells in Tumors
Ipilimumab raises the ratio of effector T cells to TREGS in the tumor, and needs to bind both cell types to work best. How it does this to each cell type differently wasn’t clear.
A study in The Journal of Experimental Medicine by Simpson et al tested this in a mouse tumor model, and found the effect depends on the tissue:
- In tumors with many infiltrating CD11b+ macrophages expressing the ADCC-activating receptor FcgRIV, TREGS were selectively depleted in an FcgR-dependent way, while effector T cells expanded.
- In lymph nodes, which have fewer of these macrophages, both effector T cell and TREG numbers increased instead.
- Tumor-associated TREGS expressed more CTLA-4 than effector T cells or lymph-node TREGS, suggesting higher CTLA-4 expression is what drives macrophage-mediated ADCC in the tumor.
Ipilimumab’s effects required both the presence of FcgRs and the TREG depletion that follows. This points to two mechanisms working together: releasing effector T cells from CTLA-4 inhibition directly, and depleting TREGS through ADCC.
A Second Study Confirms the Mechanism
A second article in the same issue of The Journal of Experimental Medicine, by Bulliard et al, looked at FcgR engagement for both Ipilimumab and an agonistic antibody called DTA-1. DTA-1 targets GITR (glucocorticoid-induced TNFR-related protein), a T cell activating receptor also found on both effector T cells and TREGs.
The study found that for both antibodies, engaging activating FcgRs to drive ADCC-mediated TREG depletion from the tumor was a major mechanism of action.
Activating GITR on effector T cells does boost cytokine production and proliferation on its own. But this agonistic effect alone wasn’t enough — it needed activating FcgR engagement too. So even though Ipilimumab (antagonistic) and DTA-1 (agonistic) work differently, FcgR-mediated ADCC of TREGs appears critical for both antibodies’ anti-tumor effects.
What This Means for Immunotherapy Development
These studies point to a few key lessons for developing tumor immunotherapies:
- A single antibody can produce multiple effects, depending on the target’s expression level, the antibody’s isotype, and which FcgR-expressing cell types are present in the tissue.
- It will be important to map out which immune cell types can mediate ADCC in different tumor types, which FcgRs they express, and how much of the target molecule they carry. That determines whether a cell type gets eliminated versus activated or inhibited.
- FcgRs are polymorphic in humans, and these genetic variations affect IgG binding affinity. Accounting for this variation will matter for personalized medicine going forward.
Further reading:
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, Roddie C, Henry JY, Yagita H, Wolchok JD, Peggs KS, Ravetch JV, Allison JP, Quezada SA. J Exp Med. 2013 Jul 29.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. Bulliard Y, Jolicoeur R, Windman M, Rue SM, Ettenberg S, Knee DA, Wilson NS, Dranoff G, Brogdon JL. J Exp Med. 2013 Jul 29.
Fcgamma receptors as regulators of immune responses. Nimmerjahn F, Ravetch JV. Nat Rev Immunol. 2008 Jan;8(1):34-47.
