TNF-Pathway Proteins Modulate Tumor Susceptibility to T-cell Attack

Cytokines such as IFNγ contribute to cytotoxic T cells’ antitumor activity, but systematic, unbiased analyses of IFNγ-independent tumor signaling pathways are lacking. Through a genome-wide CRISPR–Cas9 knockout screen of IFNγ receptor–deficient melanoma, Vredevoogd and colleagues uncovered genes that sensitized tumor cells to elimination by T cells independently of IFNγ; of these, the top hits were tumor necrosis factor (TNF) receptor–associated factor 2 (TRAF2) followed by BIRC2 (which encodes cellular Inhibitor of apoptosis 1 [cIAP1]). TRAF2 and cIAP2 are involved in the same pathway: TRAF2 recruits cIAP2 to inhibit death receptor–mediated apoptosis. Comparing patient cohorts before and after immune-checkpoint blockade therapy revealed that neither TNF expression nor mutations in TNF-pathway genes affected prognosis at baseline. This was further substantiated by in vitro dose-titration experiments, which showed that even high TNF concentrations were not cytotoxic. However, in patients who respond to immunotherapy, expression of TNF and TNF response signatures were increased. TRAF2 inactivation in melanomas was associated with receptor interacting protein kinase 1 (RIPK1) cleavage by T cells, which causes RIPK1-dependent cell death, and inactivation of TRAF2 greatly increased sensitivity of tumor cells to TNF toxicity at physiologically relevant concentrations in vitro and in vivo. Although no small-molecule inhibitor of TRAF2 is available, it is known that Fn14 stimulation by its ligand TWEAK can cause lysosomal degradation of TRAF2, and treatment with the Fn14 antibody enavatuzumab led to TRAF2 degradation and a TRAF2-dependent increase in susceptibility to T-cell cytotoxicity in two melanoma cell lines. Demonstrating the broader applicability of these findings, TRAF2 inactivation in 9 of 11 tested melanoma and lung cancer cell lines led to increased susceptibility to T-cell killing. TRAF2–cIAP complex inhibition sensitized all 11 tested cancer cell lines to T-cell killing in vitro while also increasing the efficacy of anti–PD-1 therapy in a xenograft mouse model of melanoma. These results indicate that further examination of the TNF signaling pathway in tumor cells for targets relevant to immuno-oncology may be fruitful.

Vredevoogd DW, Kuilman T, Ligtenberg MA, Boshuizen J, Stecker KE, de Bruijn B, et al. Augmenting immunotherapy impact by lowering tumor TNF cytotoxicity threshold. Cell 2019;178:585–99.E15.

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