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 at Harvard Medical School has identified that RGMB-deficient T cells can promote strong anti-tumor immunity that overcomes resistance to PD-1/PD-L1 checkpoint blockade.

The research team identified an association between upregulation of RGMb on CD8+ tumor-infiltrating T cells and resistance to PD-1/PD-L1 checkpoint blockade. RGMb on CD8⁺ T cells was found to interact with PD-L2 on dendritic cells to inhibit anti-tumor immunity mediated by PD-1/PD-L1 blockade. Accordingly, antibody-mediated blockade of RGMb or conditional deletion of RGMb in T cells combined with either PD-1 or PD-L1 blockade could promote anti-tumor immunity in mouse models of colorectal carcinoma and melanoma that were otherwise resistant to anti-PD-1 or anti-PD-L1 monotherapy. The findings demonstrate that T cells with reduced RGMb expression or activity can be sufficient to overcome resistance to immune checkpoint blockade targeting the PD-1–PD-L1 pathway.

These modified T 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 has been published in Nature.