Highlights d TNF abundance is low in tumors at baseline and in ICB nonresponding patients d CRISPR/Cas9 screen uncovers hits in the TNF pathway that sensitize to T cell attack d TRAF2 inactivation lowers tumor cytotoxicity threshold to T cell-derived TNF d Combined targeting of TRAF2/cIAP1 increases ICB impact

Immunotherapy of advanced melanoma with CTLA-4 or PD-1/PD-L1 checkpoint blockade induces in a proportion of patients long durable responses. In contrast, targeting the MAPK-pathway by selective BRAF and MEK inhibitors induces high response rates, but most patients relapse. Combining targeted therapy with immunotherapy is proposed to improve the long-term outcomes of patients. Preclinical data endorsing this hypothesis are accumulating. Inhibition of the PI3K-Akt-mTOR pathway may be a promising treatment option to overcome resistance to MAPK inhibition and for additional combination with immunotherapy.We therefore evaluated to which extent dual targeting of the MAPK and PI3K-Akt-mTOR pathways affects tumor immune infiltrates and whether it synergizes with PD-1 checkpoint blockade in a BRAFV600E/PTEN−/−-driven melanoma mouse model. Short-term dual BRAF + MEK inhibition enhanced tumor immune infiltration and improved tumor control when combined with PD-1 blockade in a CD8+ T cell dependent manner. Additional PI3K inhibition did not impair tumor control or immune cell infiltration and functionality. Analysis of on-treatment samples from melanoma patients treated with BRAF or BRAF + MEK inhibitors indicates that inhibitor-mediated T cell infiltration occurred in all patients early after treatment initiation but was less frequent found in on-treatment biopsies beyond day 15.Our findings provide a rationale for clinical testing of short-term BRAF + MEK inhibition in combination with immune checkpoint blockade, currently implemented at our institutes. Additional PI3K inhibition could be an option for BRAF + MEK inhibitor resistant patients that receive targeted therapy in combination with immune checkpoint blockade.

Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor-associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier.