Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer

Abstract

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%]) (χ2 = 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.

Figure 1.. Tissue Similarity Between Lung Tumors and Organs Affected by Autoimmune Toxic Effects

Positive associations between tumor-tissue similarity score and organ-specific immune-related adverse effects in patients with non–small cell lung carcinoma treated with nivolumab (A) or pembrolizumab (B). Pearson correlation coefficient was R = 0.71 for nivolumab and R = 0.81 for pembrolizumab, and the P value was P = .003 for nivolumab and P = .001 for pembrolizumab.

Figure 2.. Association Between Autoimmune Skin Toxic Effects and Response to Therapy

Images of a representative patient show autoimmune skin toxic effects (A) and lung tumors (B) characterized by an inflammatory infiltrate shown by CD3 immunohistochemistry (magnification ×100). C, Kaplan-Meier analysis of patients treated with PD-1 inhibitors reveals better outcome for 25 patients who developed skin toxic effects (blue line) compared with 48 other patients who did not develop skin toxic effects (orange line). One-year overall survival rate was 76% in the group with skin toxic effects and 38% in the group without skin toxic effects, with a hazard ratio of 0.29 (95% CI, 0.12-0.71) and log-rank P = .004.

Figure 3.. Sharing of T-Cell Clones in Autoimmune Skin Lesions, Lung Tumors, and Antigen-Stimulated Peripheral Blood Mononuclear Cells (PBMCs)

A, TCRβ sequences shared in the non–small cell lung carcinoma (NSCLC), skin, and sorted CD4⁺/CD8⁺ interferon (IFN)-γ⁺ T cells from PBMCs after the latter were stimulated with desmocollin 3 (DSC3) and keratin 6 (KRT6) from 1 patient. In total, 5 unique shared clones were found. The CD4⁺ clones shared with PBMCs are encircled in orange, and CD8⁺ clones shared with PBMCs are encircled in dark blue in the dot plots. B, Shared TCRβ sequences in the NSCLC, skin, and sorted CD4⁺/CD8⁺ IFN-γ⁺ T cells from PBMCs after the latter were stimulated with maspin, LL37, keratin 14 (KRT14), and DSC3 from another patient. In total, 31 unique shared clones were found (for this patient, only some of the clones are indicated).