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Overcoming Tumor-Induced Immune Suppression: From Relieving Inhibition to Providing Costimulation with T Cell Agonists

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Abstract

Recent advancements in T-cell biology and antibody engineering have opened doors to significant improvements in cancer immunotherapy. Initial success with monoclonal antibodies targeting key receptors that inhibit T-cell function such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death-ligand 1 (PD-1) have demonstrated the potency of this new class of therapy, highlighted by long-term complete responses for metastatic cancers once thought incurable. However, only a subset of patients responds to checkpoint blockade because of a multitude of factors, including an immunosuppressive tumor microenvironment and the mutational burden of the cancer. Novel antibodies, as well as ligand-immunoglobulin fusion proteins that target costimulatory immune receptors, are being developed and tested in clinical trials to further enhance the anti-tumor immune response. Many of these costimulatory receptors are in the tumor necrosis factor receptor superfamily (TNFRSF) and are expressed on multiple immune cell types, including inhibitory cells. While TNFRSFs signal through common pathways, the outcome of targeting different receptors depends on the functional status of the cell types expressing the relevant receptors. In this review, we discuss the current state of targeted costimulatory immunotherapy.

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Acknowledgements

The authors thank Annah Rolig for her careful review of this manuscript.

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Authors and Affiliations

  1. Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan St., 2N35, Portland, OR, 97213, USA

    Dana A. Emerson & William L. Redmond

  2. Molecular Microbiology and Immunology Department, Oregon Health and Science University, Portland, OR, 97239, USA

    Dana A. Emerson

Authors
  1. Dana A. Emerson
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  2. William L. Redmond
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Contributions

DE reviewed the available literature and wrote the manuscript. WLR contributed to critical review and editing of the manuscript. Both authors read and approved the final manuscript.

Corresponding author

Correspondence to William L. Redmond.

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Funding

This work was supported by the Providence Portland Medical Foundation, Susan G. Komen Grant Career Catalyst Research Grant (CCR15329664), and NIH R21CA190790.

Conflicts of interest

DE has no competing interests. WLR has received commercial research grants, consulting fees, and/or royalties from MedImmune, Bristol-Myers Squibb, Merck, Galectin Therapeutics, Nektar Therapeutics, Aeglea Biotherapeutics, IRX Therapeutics, Tesaro, Shire, and Shimadzu.

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Emerson, D.A., Redmond, W.L. Overcoming Tumor-Induced Immune Suppression: From Relieving Inhibition to Providing Costimulation with T Cell Agonists. BioDrugs 32, 221–231 (2018). https://doi.org/10.1007/s40259-018-0277-2

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