IMPORTANCE Immunotherapy with checkpoint inhibitors targeting the PD-1 (programmed cell death 1) axis has brought notable progress in patients with non-small cell lung cancer (NSCLC) and other cancers. However, autoimmune toxic effects are frequent and poorly understood, making it important to understand the pathophysiologic processes of autoimmune adverse effects induced by checkpoint inhibitor therapy. OBJECTIVE To gain mechanistic insight into autoimmune skin toxic effects induced by anti-PD-1 treatment in patients with non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted from July 1, 2016, to December 31, 2018. Patients (n = 73) with non-small cell lung cancer who received anti-PD-1 therapy (nivolumab or pembrolizumab) were recruited from 4 different centers in Switzerland (Kantonsspital St Gallen, Spital Grabs, Spital Wil, and Spital Flawil). Peripheral blood mononuclear cells, tumor biopsy specimens and biopsies from sites of autoimmune skin toxic effects were collected over a 2-year period, with patient follow-up after 1 year. MAIN OUTCOMES AND MEASURES Response to treatment, overall survival, progression-free survival, and development of autoimmune toxic effects (based on standard laboratory values and clinical examinations). RESULTS Of the cohort of 73 patients with NSCLC (mean [SD] age, 68.1 [8.9] years; 44 [60%] men), 25 (34.2% [95% CI, 24.4%-45.7%]) developed autoimmune skin toxic effects, which were more frequent in patients with complete remission or partial remission (68.2% [95% CI, 47.3%-83.6%]) than those with progressive or stable disease (19.6% [95% CI, 11.0%-32.5%]) (χ 2 = 14.02, P < .001). Nine T-cell antigens shared between tumor tissue and skin were identified. These antigens were able to stimulate CD8 + and CD4 + T cells in vitro. Several of the antigen-specific T cells found in blood samples were also present in autoimmune skin lesions and lung tumors of patients who responded to anti-PD-1 therapy. CONCLUSIONS AND RELEVANCE These findings highlight a potential mechanism of checkpoint inhibitor-mediated autoimmune toxic effects and describe the association between toxic effects and response to therapy; such an understanding will help in controlling adverse effects, deciphering new cancer antigens, and further improving immunotherapy.

These results support the utility of SAFB for pretransplant risk assessment and organ allocation, and suggest that improvement of the positive predictive value of HLA-DSA defined by SAFB will require an enhanced definition of pathogenic factors of HLA-DSA.

Glycolysis is linked to the rapid response of memory CD8 T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8 T cells are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3β at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8 T cells to rapidly acquire effector function.

In 90% of patients, pretransplant HLA-DSA are composed of isolated strong or a mixture of strong and weak/no complement-activating IgG subclasses. Because outcomes in these two groups were similar, pretransplant IgG subclass analysis is likely not providing substantial value beyond the standard IgG SAFB assay for pretransplant risk stratification.

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