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  • Review Article
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Fcγ receptors and immunomodulatory antibodies in cancer

Nature Reviews Cancer volume 24, pages 51–71 (2024)Cite this article

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Abstract

The discovery of both cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) as negative regulators of antitumour immunity led to the development of numerous immunomodulatory antibodies as cancer treatments. Preclinical studies have demonstrated that the efficacy of immunoglobulin G (IgG)-based therapies depends not only on their ability to block or engage their targets but also on the antibody’s constant region (Fc) and its interactions with Fcγ receptors (FcγRs). Fc–FcγR interactions are essential for the activity of tumour-targeting antibodies, such as rituximab, trastuzumab and cetuximab, where the killing of tumour cells occurs at least in part due to these mechanisms. However, our understanding of these interactions in the context of immunomodulatory antibodies designed to boost antitumour immunity remains less explored. In this Review, we discuss our current understanding of the contribution of FcγRs to the in vivo activity of immunomodulatory antibodies and the challenges of translating results from preclinical models into the clinic. In addition, we review the impact of genetic variability of human FcγRs on the activity of therapeutic antibodies and how antibody engineering is being utilized to develop the next generation of cancer immunotherapies.

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Fig. 1: Human Fcγ receptors, their expression pattern and affinity for therapeutic IgG1, IgG2 and IgG4.
Fig. 2: Fcγ receptor mRNA expression in key immune subsets from patients with non-small-cell lung cancer, renal cell carcinoma and colorectal cancer.
Fig. 3: The mechanism of action of monoclonal antibodies directed against T cell immune checkpoints in cancer.
Fig. 4: The mechanism of action of monoclonal antibodies directed against T cell co-stimulatory receptors ICOS and CD40 in cancer.
Fig. 5: The mechanism of action of monoclonal antibodies directed against T cell co-stimulatory receptors OX40 and 4-1BB in cancer.

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Data availability

The single-cell RNA sequencing (scRNA-seq) analysis shown in Fig. 2 used publicly available data from the following sources: GSE121638 (ref. 264), GSE131907 (ref. 265), GSE127465 (ref. 266), GSE178341 (ref. 267), GSE148071 (ref. 268), SRZ190804 (ref. 269), (https://github.com/czbiohub/scell_lung_adenocarcinoma), (http://blueprint.lambrechtslab.org), Braun et al.270, Bi et al.271 (https://singlecell.broadinstitute.org/single_cell/study/SCP1288/tumour-and-immune-reprogramming-during-immunotherapy-in-advanced-renal-cell-carcinoma#study-summary), Chan et al.272 (https://data.humantumoratlas.org/) and Cheng et al.273 (data accessed via a request to corresponding author).

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Acknowledgements

S.A.Q. is funded by a Cancer Research UK (CRUK) Senior Cancer Research Fellowship (C36463/A22246) and a CRUK Biotherapeutic Program grant (C36463/A20764). This work was undertaken at UCL with support from the CRUK-CoL Centre (C7893/A26233).

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Author notes

  1. These authors contributed equally: Felipe Galvez-Cancino, Alexander P. Simpson.

Authors and Affiliations

  1. Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK

    Felipe Galvez-Cancino, Alexander P. Simpson, Cristobal Costoya, Ignacio Matos, Karl S. Peggs & Sergio A. Quezada

  2. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK

    Felipe Galvez-Cancino, Alexander P. Simpson, Danwen Qian, Kevin Litchfield & Sergio A. Quezada

  3. Tumour Immunogenomics and Immunosurveillance Laboratory, University College London Cancer Institute, London, UK

    Danwen Qian & Kevin Litchfield

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Contributions

F.G-C., A.P.S., C.C., I.M., D.Q. and K.L. researched data for the article. F.G-C., A.P.S., C.C., I.M., K.S.P., K.L. and S.A.Q. contributed substantially to discussion of the content. F.G-C., A.P.S. and S.A.Q. wrote the article. F.G-C., A.P.S., K.S.P. and S.A.Q. reviewed and/or edited the manuscript before submission.

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Correspondence to Sergio A. Quezada.

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Nature Reviews Cancer thanks Rony Dahan who co-reviewed with Yahel Avraham, Jeanette Leusen and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Supplementary information

Glossary

Anaphylaxis

A rare but severe allergic reaction that is caused by the systemic release of inflammatory mediators and cytokines resulting in non-specific immune activation.

Antibody-dependent cellular cytotoxicity

(ADCC). Engagement of activating Fcγ receptors (FcγRs) can result in the release of cytotoxic granules to kill the target cell. Predominantly mediated by natural killer (NK) cells, granulocytes and myeloid cells.

Antibody-dependent cellular phagocytosis

(ADCP). Engagement of activating Fcγ receptors (FcγRs) can result in the phagocytosis of opsonized target cells, resulting in their destruction. Predominantly mediated by myeloid cells and granulocytes.

Antibody–drug conjugates

Antibodies chemically tagged to a cytotoxic drug that are designed to bind to a specific antigen and release the drug to the target cell.

Anti-drug antibodies

(ADAs). The immunogenicity of a drug can provoke the immune system into generating an adaptive immune response against the said drug. This can result in antibodies that can neutralize the drug’s mechanism of action.

Assembloids

Organoid-like cultures that contain the tumour and associated microenvironment, maintained in a 3D structure ex vivo.

Bispecific antibodies

Antibodies with two distinct binding sites directed against two different antigens.

Copy number variable regions

(CNRs). A cluster of two or more genes have deletions or duplications of the gene loci, altering protein expression.

Copy number variations

A specific segment of DNA is repeated within the genome of an individual and shows variation in the number of repeats across a population.

Germinal centre

A structure present in lymphoid organs where activated B cells diversify their immunoglobulin genes by somatic hypermutation to generate high-affinity antibodies.

IgG subclass

Defined by the differences in the length of the hinge and number of disulfide bonds, the subclass affects the binding affinity to different Fcγ receptors (FcγRs) and influences the potency of immunoglobulin G (IgG) effector functions.

Immune-proficient patient-derived xenografts

(Immune-PDX). An in vivo system utilizing immunocompromised mice to engraft fragments of a human tumour (and the accompanying microenvironment) for experimentation and therapeutic testing.

Immunomodulatory antibodies

Therapeutic immunoglobulin G (IgG) antibodies designed to bind to immune cells, to either block an inhibitory signal or agonize an activating receptor and enhance the immune response.

Kupffer cells

Resident liver macrophage cells that maintain liver function and act as the first line defence of the innate immune system.

Patient-derived explants

(PDE). An ex vivo system designed to maintain fragments of human tumours (and the accompanying microenvironment) for experimentation and therapeutic testing.

Pseudogene

A non-functional segment of DNA that resembles functional genes containing coding deficiencies such as frameshift mutations or premature stop codons.

Single nucleotide polymorphisms

(SNPs). A single nucleotide change within a protein sequence (present in >1% population) that affects the protein function and, potentially, the patient phenotype.

Surface plasmon resonance

(SPR). An optical technique used to measure molecular interactions. The refractive index of polarized light changes upon the binding of the analyte to the ligand, producing a sensorgram which allows the interpretation of the binding kinetics of two molecules.

Tumour-targeting antibodies

Therapeutic immunoglobulin G (IgG) antibodies designed to bind specifically to a tumour cell and elicit destruction of the cell.

Valency

The number of binding sites present on the antibody to enable binding to the antigen. Immunoglobulin G (IgG) typically has a valency of two (bivalent).

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Galvez-Cancino, F., Simpson, A.P., Costoya, C. et al. Fcγ receptors and immunomodulatory antibodies in cancer. Nat Rev Cancer 24, 51–71 (2024). https://doi.org/10.1038/s41568-023-00637-8

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