The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy

Abstract

In recent years monoclonal antibodies (mAbs) able to reinvigorate anti-tumor T cell immunity have heralded a paradigm shift in cancer treatment. The most high profile of these mAbs block the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients across a range of tumor types. However, it is becoming increasingly clear that failure of some patients to respond to checkpoint inhibition is due to inadequate T-cell priming. For full T-cell activation two signals must be received and ligands providing the second of these signals, termed costimulation, are often lacking in tumors. Members of the TNF receptor superfamily (TNFRSF) are key co-stimulators of T cells during infection and there has been an increasing interest in harnessing these receptors to augment tumor immunity. We here review the immunobiology of two particularly promising TNFRSF target receptors, CD27 and OX40, and their respective ligands CD70 and OX40L, focusing on their role within a tumor setting. We describe the influence of CD27 and OX40 on human T cells based on in vitro studies and on the phenotypes of several recently described individuals exhibiting natural deficiencies in CD27/CD70 and OX40. Finally we review key literature describing progress in elucidating the efficacy and mode of action of OX40- and CD27-targeting mAbs in pre-clinical models and provide an overview of current clinical trials targeting these promising receptor/ligand pairings in cancer.

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ORCID for Aymen Al-Shamkhani: orcid.org/0000-0003-0727-4189

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