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The importance of exosomal PDL1 in tumour immune evasion

Nature Reviews Immunology volume 20, pages 209–215 (2020)Cite this article

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Abstract

The interaction of programmed cell death 1 ligand 1 (PDL1) with its receptor programmed cell death 1 (PD1) inhibits T cell responses, and blockade of this interaction has proven to be an effective immunotherapy for several different cancers. PDL1 can be expressed on the surface of tumour cells, immune cells and other cells in the tumour microenvironment but is also found in extracellular forms. Recent studies have explored the importance of different forms of extracellular PDL1, such as on exosomes or as a freely soluble protein, and have shown that PDL1-expressing exosomes can inhibit antitumour immune responses. In patients with melanoma, exosomal PDL1 is also a marker of immune activation early after initiation of therapy with PD1-blocking antibodies and predicts a clinical response to PD1 blockade. In this Progress article, we highlight recent insights into the role of exosomal PDL1 in immune oncology and how it may be useful as a biomarker for the management of cancer or to define a subset of patients who would benefit from therapeutics that block exosome production.

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Fig. 1: Cells expressing PDL1 can produce multiple forms of soluble (extracellular) PDL1.

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Acknowledgements

This work was supported by the Dana-Farber/Harvard Cancer Center Kidney Cancer SPORE P50CA101942 (to G.J.F. and K.M.M.), a Department of Defense Early Investigator Idea Development Award W81XWH1810500 (to K.M.M.), and grants P50CA206963 and P01AI056299 (to G.J.F.).

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  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Dhouha Daassi, Kathleen M. Mahoney & Gordon J. Freeman

  2. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Kathleen M. Mahoney

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Correspondence to Gordon J. Freeman.

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Competing interests

G.J.F. has patents or pending royalties on the PD1–PDL1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos and NextPoint. The other authors declare no competing interests.

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Glossary

Companion diagnostic

A biomarker assay that has been established and validated as a predictive biomarker to direct treatment decisions. A positive score in a companion diagnostic assay is required by the US Food and Drug Administration for treatment with its associated therapeutic. For example, >50% PDL1+ tumour cells for treatment of non-small-cell lung cancer with pembrolizumab monotherapy. By contrast, a complementary diagnostic assay is used by clinicians to aid in risk–benefit analysis of treatment decisions but it is not required for use of the therapeutic.

Exosomes

Small extracellular vesicles present in almost all extracellular fluids, including blood, urine, cerebrospinal fluid and saliva. Exosomes are produced in the endosomal compartment, released from the extracellular membrane and are generally smaller (30–100 nm) than other types of extracellular vesicle. Exosomes can communicate between cells by fusing with a target cell and unloading the exosome contents into the cell.

Microvesicles

Vesicles (100–1000 µm) that are larger than exosomes and not produced through the exocytic pathway (as are exosomes) but by budding from the cell surface. Microvesicles are isolated at lower centrifugation speeds than exosomes and share some functions with exosomes.

TRAMP-C2 model

Transgenic adenocarcinoma of the mouse prostate (TRAMP) is a mouse model of prostate cancer in which prostate cancers arise orthotopically because SV40 large T antigen is expressed in a prostate-restricted manner, locally downregulating the tumour suppressor molecules p53 and RB. The TRAMP-C2 cell line is generated from a spontaneously arising TRAMP tumour and is a transplantable model of prostate cancer in syngeneic C57BL/6 mice.

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Daassi, D., Mahoney, K.M. & Freeman, G.J. The importance of exosomal PDL1 in tumour immune evasion. Nat Rev Immunol 20, 209–215 (2020). https://doi.org/10.1038/s41577-019-0264-y

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