Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies

By K. Peggs, Sergio A. Quezada, C. Chambers, A. Korman, James P. Allison. Journal of Experimental Medicine, 2009

936 citations recorded by the source corpus.

Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (Teff) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti–CTLA-4 antibodies during cancer immunotherapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/fd20d12020285e95c0f8be12c3c85d6638775cf9

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Citations in the corpus

The blockade of immune checkpoints in cancer immunotherapy (2012, background): “Even though CTLA4 is expressed by activated CD8 + effector T cells, the major physiological role of CTLA4 seems to be through distinct effects on the two major subsets of CD4 + T cells: downmodulation of helper T cell activity and enhancement of regulatory T (T Reg ) cell immunosuppressive activ”
Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells (2016, background): “Recent experimental evidence shows that anti-CTLA-4 mAb efficacy depends on FcgR-mediated depletion of CD4+ regulatory T cells (Treg cells) within the tumor microenvironment (Peggs et al., 2009; Selby et al., 2013; Simpson et al., 2013; TwymanSaint Victor et al., 2015).”
Immune Checkpoint Targeting in Cancer Therapy: Towards Combination Strategies with Curative Potential (2015, background): “Second, taking into consideration that CTLA-4 inhibited CD28-mediated costimulation by a cellintrinsic mechanism (Peggs et al., 2009), its blockade could allow for enhanced T cell costimulation, which in turn would increase the efficacy of tumor vaccines, as well as agents that kill tumor cells…”
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma (2013, background): “We previously demonstrated that unicompartmental binding of CTLA-4 to the T eff cell compartment is capable of inducing tumor protection in some mice (Peggs et al., 2009), although protection was significantly reduced when compared to targeting both the T eff and T reg cell compartments.”
PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors (2010, background): “GP100 (25), Trp-1 (455, 481, and 522), and Trp-2 (181) peptides were obtained from Biosynthesis, Inc. and used at a final concentration of 10 μm.”
Interleukin-35-mediated induction of a novel regulatory T cell population (2010, methodology): “Using B16 melanoma and MC38 colorectal adenocarcinoma as model system”
Dual Blockade of PD-1 and CTLA-4 Combined with Tumor Vaccine Effectively Restores T Cell Rejection Function in Tumors (2013, background): “Mechanisms regulating immune activation in cancer progression have been extensively investigated (4-16).”
CTLA-4 and PD-1/PD-L1 Blockade: New Immunotherapeutic Modalities with Durable Clinical Benefit in Melanoma Patients (2013, background): “Furthermore, CTLA-4 is expressed by regulatory T cells (Treg) and memory CD4 cells and these cells may also be targeted by CTLA-4 blockade (16).”
Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012, background): “Importantly, CTLA-4 blockage has already shown promising outcomes in clinical trials for metastatic melanoma, presumably due to its effects on both effector T cells and Tregs (Peggs et al., 2009).”
Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts (2010, methodology): “Finally, to determine the cellular targets of anti–CTLA-4, we used recipient mice expressing human CTLA-4 instead of mouse CTLA-4 (Peggs et al., 2009).”
Dendritic-cell-based therapeutic cancer vaccines. (2013, background): “…CD103 [Le Floc’h et al., 2007] and CD49a [Sandoval et al., 2013]), and (4) high expression of costimulatory molecules (e.g., CD137 [Wilcox et al., 2002]) or low expression of inhibitory molecules (e.g., cytotoxic T lymphocyte antigen 4 [CTLA-4] [Peggs et al., 2009] or PD-1 [Freeman et al., 2006]).”