Immune checkpoint blockade therapies targeting PD-1 or PD-L1 have been approved for more than 25 different tumors. However, many patients do not respond to PD-1/PD-L1 checkpoint blockade. The Sharpe lab has identified that dendritic cells (DCs) with reduced PD-L2 expression can promote strong anti-tumor immunity, which can overcome resistance to PD-1/PD-L1 checkpoint blockade.

A research team at Harvard Medical School identified an association between the upregulation of PD-L2 expression on DCs and resistance to PD-1/PD-L1 checkpoint blockade. PD-L2^hi DCs were found to interact with RGMb on CD8⁺ T cells to inhibit anti-tumor immunity mediated by PD-1/PD-L1 blockade. Accordingly, inhibition of PD-L2 in combination with either PD-1 or PD-L1 blockade could promote anti-tumor immunity in mouse models of colorectal carcinoma, bladder carcinoma, breast adenocarcinoma, and melanoma that did not respond to anti-PD-1 or anti-PD-L1 monotherapy. Treatment with Pdl2 knockout DCs alone could also promote a strong anti-tumor response in a mouse model of melanoma, demonstrating that PD-L2^lo DCs can be sufficient to activate CD8⁺ T cells to promote anti-tumor immunity.

These modified dendritic cells have potential for therapeutic applications in cancer immunotherapy, including the treatment of patients who do not respond to PD-1/PD-L1 checkpoint inhibition therapy.

The research is published in Nature.