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CD28 co-stimulation: novel insights and applications in cancer immunotherapy

Nature Reviews Immunology volume 24, pages 878–895 (2024)Cite this article

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Abstract

Substantial progress in understanding T cell signalling, particularly with respect to T cell co-receptors such as the co-stimulatory receptor CD28, has been made in recent years. This knowledge has been instrumental in the development of innovative immunotherapies for patients with cancer, including immune checkpoint blockade antibodies, adoptive cell therapies, tumour-targeted immunostimulatory antibodies, and immunostimulatory small-molecule drugs that regulate T cell activation. Following the failed clinical trial of a CD28 superagonist antibody in 2006, targeted CD28 agonism has re-emerged as a technologically viable and clinically promising strategy for cancer immunotherapy. In this Review, we explore recent insights into the molecular functions and regulation of CD28. We describe how CD28 is central to the success of current cancer immunotherapies and examine how new questions arising from studies of CD28 as a clinical target have enhanced our understanding of its biological role and may guide the development of future therapeutic strategies in oncology.

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Fig. 1: Timeline of CD28-related discoveries.
Fig. 2: Expression and function of CD28.
Fig. 3: CD28 in the tumour microenvironment.

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Acknowledgements

The authors thank the careful review by their colleagues L. Appleman, A. Ross, A. de Vallejo, M. Flajnik, E. Geoghegan and C. B. Thompson. This work was supported, in part, by grants from the National Institute for Allergy and Infectious Diseases (NIAID) (R01 AI155499 to S.H.O.) and by the National Cancer Institute (NCI) Roswell Park Cancer Center Support Grant (P30 CA016056), as well as that to the University of Pittsburgh Hillman Cancer Center (P30 CA047904-35).

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Authors and Affiliations

  1. Department of Surgery, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, USA

    Michael T. Lotze

  2. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

  3. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Michael T. Lotze

  4. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Scott H. Olejniczak

  5. Regeneron Pharmaceuticals, Tarrytown, NY, USA

    Dimitris Skokos

Authors
  1. Michael T. Lotze
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  2. Scott H. Olejniczak
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  3. Dimitris Skokos
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Michael T. Lotze, Scott H. Olejniczak or Dimitris Skokos.

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Competing interests

M.T.L. is the chairman of the strategic advisory board and has ownership interest in iRepertoire, Inc; he is a member of the scientific advisory boards of KSQ, Inc.; BioCytics; Zai Laboratories; Appel Sauce, Studios; and the Ludwig Institute. S.H.O. declares no competing interests. D.S. is a full-time employee and shareholder of Regeneron Pharmaceuticals, Inc.

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Nature Reviews Immunology thanks Tadashi Yokosuka and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Adoptive cell therapies

Immunotherapeutic strategy in which immune cells, often CAR T cells or TILs, that have been expanded and prepared ex vivo are infused into a patient.

Central supramolecular activation cluster

The centre of an immune synapse between an immune cell and a target cell, comprising recruited receptor molecules such as the T cell receptor and CD28. Phosphatases that constrain immune activation are typically found outside this central area.

Chimeric antigen receptor

(CAR). A synthetic receptor genetically engineered into immune cells to redirect their specificity towards a desired cell-surface antigen in an MHC-independent manner; clinically available CARs contain either a CD28 or 4-1BB co-stimulatory domain.

Combination cancer immunotherapy

A strategy to overcome resistance to existing immunotherapies such as immune checkpoint blockade (ICB). One approach involves bispecific and/or trispecific antibodies targeting CD3 and/or co-stimulatory molecules such as CD28 together with ICB or other standard treatments. Combinations of different antibody formats and/or cell therapies are also being explored.

Cytokine release syndrome

(CRS). Toxicity associated with immune overactivation. This was first observed in the setting of bacteria-induced toxic shock syndrome, following high-dose IL-2 administration and following the delivery of CD28-superagonist antibody; now, it is also commonly observed following CAR T cell administration to patients with haematological cancer and in the setting of severe COVID-19.

Immune checkpoint blockade

(ICB). The therapeutic use of antagonistic antibodies to cell-surface proteins that limit T cell activation (immune checkpoints, such as PD1 and PD-L1), thereby promoting CD28 signalling and antitumour immunity.

Immune effector cell-associated neurotoxicity syndrome

(ICANS). A clinical syndrome characterized by a range of neuropsychiatric symptoms that occurs following certain types of immunotherapy that induce a strong T cell response; it is probably caused by disruption to the blood–brain barrier as a result of inflammation induced by cytokine release syndrome.

Immune synapse

The physical interface between an antigen-presenting cell or target cell and a T cell.

Senescence

A cell state in which mature cells are limited in their proliferation and functions, associated with loss of CD28 expression in T cells.

T cell exhaustion

The progressive loss of effector function and memory potential of T cells owing to persistent T cell receptor signalling.

T cell-activating immunotherapies

Tumour-infiltrating lymphocytes can be activated by antibodies or by small-molecule inhibitors of E3 ligases that limit full T cell activation. Cytokines such as IL-2 or IL-15 can drive T cell proliferation.

Tumour microenvironment

(TME). The TME has a ‘tissue-like’ organization comprising, in addition to the tumour itself, tumour neovasculature, stromal support elements, and recruited myeloid and lymphoid cells. It often contains immunosuppressive elements including prostaglandins, immunosuppressive cytokines and metabolic alterations such as hypoxia and an acidic milieu.

Tumour-associated antigen

(TAA). Typically, a protein or glycoprotein that is found at greater abundance on tumour cells than on normal cells (for example, Her2/Neu, mesothelin and CEA).

Tumour-infiltrating lymphocytes

(TILs). Lymphocytes found within tumours that are generally associated with improved prognosis in patients with cancer. Typically, tumours have one of three TIL phenotypes: inflamed (presence of TILs), excluded (TILs at a stromal barrier) or desert (absence of TILs).

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Lotze, M.T., Olejniczak, S.H. & Skokos, D. CD28 co-stimulation: novel insights and applications in cancer immunotherapy. Nat Rev Immunol 24, 878–895 (2024). https://doi.org/10.1038/s41577-024-01061-1

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