PD-1/LAG-3 Dysfunctionality Signatures in Human Cancers

Abstract

ABSTRACTA significant number of cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD- 1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers with high T-cell infiltration. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic and epigenetic pathways. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. These results uncovered distinct degrees of T-cell dysfunctionality. Global changes were cross-evaluated among T- cell lines with multiomic biopsy data to identify genetic, metabolic, and proteomic programmes regulated by PD-1/LAG-3 dysfunctionality. One of these relied on differential regulation of E3 ubiquitin ligases CBL-B and C-CBL. PD-1/LAG-3 co-blockade with a bispecific drug under clinical development but not with a combination of anti-PD-1/anti-LAG-3 antibodies achieved both CBL-B and C-CBL inhibition, reverting T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD- 1 blockade.