Proteomics of immune cells from liver tumors reveals immunotherapy targets

Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, as well as monocyte/macrophages, and CD4+ and CD8+ T cells isolated from tumors, livers, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2 is upregulated in chronically activated CD8+ T cells in tumors but is not present during the canonical T cell activation program. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver). Overall design: Primary human CD8 T cells were stimulated with plate bound antibodies to CD3 and CD28 plus IL2 for 14 days (Chronic stimulation). In addition, CD8 T cells were activated for 72h and then cultured in complete medium with IL2 for 9 days (Transient activation) or T cells were activated for 72h, cultured for 8 days with IL2 and then re-stimulated for 72h (Re-activated).