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%]) (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.

Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies

“…While a limited transformation is too weak in itself to provoke an effective T cell attack, the immune checkpoint blockade unleashes T cells against "altered-self" and tumors resulting in better overall survival [18]. This is consistent with the findings of Berner et al [19], in non-small cell lung cancer. They demonstrated that T cells recognize and target shared tumor and skin antigens during checkpoint inhibitor therapy resulting in autoimmune-mediated skin toxicity and tumor regression.…”

A review of cancer immunotherapy toxicity

“…Studies have suggested that irAEs may develop through the targeting of antigens shared by normal and tumor tissue. A prospective study of autoimmune dermatologic toxicity in patients who received anti–PD‐1 therapy for NSCLC described 9 T‐cell antigens that were shared between tumor tissue and skin, suggesting that T cells targeting cancer cells may also target normal tissues with shared antigens . Similarly, a case series of ICI‐induced myocarditis found high levels of muscle‐specific antigens in tumors from 2 patients who developed myocarditis, suggesting that myocarditis may develop through T‐cell targeting of a shared antigen expressed by tumor, skeletal muscle, and heart .…”

Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis

“…A number of recent studies has supported this hypothesis by showing favorable outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma who developed various irAEs in response to immune checkpoint inhibition [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. However, a definite conclusion has not been drawn based on the findings from each single study, as contradictory results exist [23][24][25][26][27][28][29][30][31][32][33][34][35].…”