Cancer immunotherapy restores and/or enhances effector function of CD8+ T cells in the tumor microenvironment1,2.,CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways3,4.,Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation5,6.,Although it was mechanistically illuminated in vitro7,8, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios9,10.,However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown.,Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy.,Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis.,In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis.,Expression of system xc- is negatively associated with CD8+ T cell signature, IFNγ expression, and cancer patient outcome.,Transcriptome analyses before and during nivolumab therapy reveal that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8.,Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism.,Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.
This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma.,In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study.,Kaplan-Meier analyses were performed to estimate and to compare overall survival.,Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups.,In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans.,In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)).,The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3-5.7).,Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase (P<0.001), administered therapy (neurosurgery or SRS vs other, P=0.002), number of brain metastases (single vs multiple, P=0.032) and presence of bone metastasis (false vs true, P=0.044).,Three prognostic groups with significantly different overall survival were identified.,Candidates for local treatment (group I) had the longer median survival (9 months).,Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase.,Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma.,Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.