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.

Immune checkpoint inhibitors have led to considerable therapy improvement in cancer patients. Autoimmune side effects including skin reactions are frequently observed. In melanoma, those include rash and vitiligo and were shown to be associated with a prolonged overall survival. Little is known about skin reactions in non-small cell lung cancer (NSCLC) patients during immunotherapy. Here, we retrospectively investigated immune-related adverse skin reactions (irAEs) in 40 patients with metastatic NSCLC treated with the anti-PD-1 antibody nivolumab. 7 out of 40 patients (17%) developed an irAEs. Skin irAEs correlated with tumor responses in 5 of 12 responders (42%) as compared to 2 of 27 non-responders (7%). Histologically, scaly plaques showed dermatitis consisting mainly of lymphocytes. We observed a positive correlation between skin irAEs and tumor responses in patients with NSCLC treated with nivolumab. Patterns of lymphocytic skin infiltration differed depending on the histological tumor subtype (adenocarcinoma versus squamous cell carcinoma NSCLC).

Background: Checkpoint inhibitors (CIs) are highly effective but can induce severe immune-related adverse events (irAEs), which cannot be predicted. We investigated whether human leukocyte antigen (HLA) genes predispose to developing of irAEs during therapy and thus hold a predictive role. Methods: We established a prospective observational single-centre study and collected data from patients with either metastatic nonesmall cell lung cancer (NSCLC) or metastatic melanoma, who were treated with antiePD-1 (programmed cell death receptor 1), anti-CTLA4 (cytotoxic T-lymphocyteeassociated protein 4) or both CIs combined. Data include irAEs and ranges from 15th July 2016 until 10th May 2018. In addition, we performed HLA typing via next generation sequencing. Results: We enrolled 102 patients (median [range] age, 68 [62e74] years) with metastatic cancer in our study who received CI therapy. Of these patients, 59 (58%) developed one or more irAEs, among which pruritus (n Z 32 (54%)) and rash (n Z 24 (41%)) had the highest rates. We did not find evidence for a single HLA gene being associated with all irAEs (all P > .05). When assessing each irAE individually, we found a significant association between HLA-DRB1*11:01 and pruritus (OR Z 4.53, X 2 1,95 Z 9.45, P < .01) as well as a nominally

This database study compares surveillance data on immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors to determine whether irAEs experienced during anti–PD-1 therapy correlate with tumor mutational burden across 18 cancer types.