Editors' ChoiceCancer

PD-L2 in follicular lymphoma: Sidekick or star?

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Science Translational Medicine  18 Sep 2019:
Vol. 11, Issue 510, eaaz2898
DOI: 10.1126/scitranslmed.aaz2898

Abstract

Immune profiling of follicular lymphoma reveals a role for PD-L2 expression in predicting early progression and survival.

Blockade of the programmed death 1 (PD-1) axis represents the most widely used immunotherapeutic advance in modern oncology. In a simplistic model, binding of the immune checkpoint molecule PD-1 on T lymphocytes to its cognate ligands programmed death ligand 1 (PD-L1) and PD-L2 on tumor cells dampens T cell antitumor activity. Most therapeutic strategies to reverse this immune suppression have focused on inhibitors of PD-1 and PD-L1, and high PD-L1 expression is generally a poor prognostic feature that correlates (imperfectly) with the activity of these agents. Tobin et al. now show an intriguing role for the “other” PD ligand, PD-L2, in determining the outcome in follicular lymphoma (FL). FL is an indolent lymphoma characterized by a remitting and relapsing course with long overall survival. However, patients who experience progression of disease within 24 months of diagnosis (POD24) have a poor outcome. The authors performed an immunophenotyping of 132 FL cases in a discovery cohort and identified PD-L2 expression to have the strongest correlation with survival in a multivariate analysis. Interestingly, it was not high but low PD-L2 that was associated with worse survival. Further analysis through flow sorting showed that PD-L2 in these tumors was not on the malignant B cells but was instead expressed in the immune infiltrate. Low PD-L2 therefore was a marker of low immune infiltration in these tumors and correlated with early progression in two independent validation cohorts. These patients were treated with conventional chemotherapy and not immune checkpoint blockade, adding evidence to the importance of immunogenic phenomena in chemotherapy efficacy.

Studies in a clinically relevant subgroup of cases, with robust replication in independent cohorts, offer a good foundation for subsequent “bedside to bench” translational research. Here, the findings of Tobin et al. raise several fascinating biological questions: Why is PD-L2 expression on nonmalignant immune cells important for survival in FL? What immune cell types in FL express PD-L2, and why is PD-L2 expression more prognostic than other ligands (including PD-L1)? Is this true of other cancers as well? Lastly, are there interventions that can increase the infiltration of PD-L2–positive immune cells into tumors? It may not yet have attained star status, but it seems clear that PD-L2 is no sidekick in the story of immune evasion in cancer.

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