The inhibitory checkpoint, PD-L2, is a target for effector T cells: Novel possibilities for immune therapy

Shamaila Munir Ahmad, Evelina Martinenaite, Morten Holmström, Mia Aaboe Jørgensen, Özcan Met, Claudia Nastasi, Uffe Klausen, Marco Donia, Lars Møller Pedersen, Lars Munksgaard, Niels Ødum, Anders Woetmann, Inge Marie Svane, Mads Hald Andersen

30 Citations (Scopus)


Cell surface molecules of the B7/CD28 family play an important role in T-cell activation and tolerance. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied whereas PD-L2 has received less attention. However, recently the expression of PD-L2 was described to be independently associated with clinical response in anti-PD1-treated cancer patients. Here, we investigated whether PD-L2 might represent a natural target that induces specific T cells. We identified spontaneous specific T-cell reactivity against two epitopes located in the signal peptide of PD-L2 from samples from patients with cancer as well as healthy individuals ex vivo. We characterized both CD8+ and CD4+ PD-L2-specific T cells. Interestingly, the epitope in PD-L2 that elicited the strongest response was equivalent to a potent HLA-A2-restricted epitope in PD-L1. Importantly, PD-L1-specific and PD-L2-specific T cells did not cross-react; therefore, they represent different T-cell antigens. Moreover, PD-L2-specific T cells reacted to autologous target cells depending on PD-L2 expression. These results suggested that activating PD-L2 specific T cells (e.g., by vaccination) might be an attractive strategy for anti-cancer immunotherapy. Accordingly, PD-L2 specific T cells can directly support anti-cancer immunity by killing of target cells, as well as, indirectly, by releasing pro-inflammatory cytokines at the microenvironment in response to PD-L2-expressing immune supressive cells.

Original languageEnglish
Issue number2
Pages (from-to)e1390641
Publication statusPublished - 2018


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