{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:42:49Z","timestamp":1790131369783,"version":"4.0.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Immune checkpoint inhibitors (ICIs) have dramatically improved survival in advanced gastrointestinal (GI) cancer patients, but also resulted in immune-related adverse events (irAEs). This study aimed to evaluate serological biomarkers of irAEs and treatment response in GI cancer patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>Metastatic GI cancer patients were enrolled between August 1, 2015, and July 31, 2017. Serum samples were collected at baseline, and a panel of 59 serum biomarkers was tested. The occurrence of irAEs was analyzed, and serological biomarker expression was correlated with irAE incidence and prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Fifty-one patients were enrolled, of whom 47.1% (24\/51) were diagnosed with irAEs, including 4 patients (7.8%) with grade 3-5 irAEs. The most common irAE was thyroiditis (9\/51, 17.6%), followed by colitis (7\/51, 13.7%). The expression of CD28 (P = 0.042), IL-4 (P = 0.033), IL-15 (P = 0.024) and PD-L1 (P = 0.018) was significantly elevated in patients with grade 3-5 irAEs. For organ-specific irAEs, IL-6 levels were higher in patients with thyroiditis and colitis, while IL-22 and SCF levels were higher in patients with colitis. Increased IL-1\u03b1, IL-21, LIF, and PIGF-1 levels were significantly associated with myositis incidence, while the serum levels of six cytokines (BTLA, GM-CSF, IL-4, PD-1, PD-L1 and TIM-3) were higher in patients with rash. Prognostic analysis showed that patients with irAEs had better tumor response (P = 0.029), improved PFS (median survival: undefined vs. 2.1 months, P = 0.002), and extended OS (median survival: undefined vs. 4.3 months, P = 0.003). The prognostic value of irAEs was only significant in patients who received anti-PD-1 inhibitors, but not in those who received anti-PD-L1 inhibitors. Besides, elevated BTLA (median OS: not reached vs. 7 months; P = 0.0168) and PD-1 (median OS: not reached vs. 7 months; P = 0.0223) concentrations were associated with longer OS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Serological proteins are promising markers for predicting immune-related toxicity and prognosis in GI cancer patients. Organ-specific irAEs have various cytokine profiles. Although further validation is needed before clinical application, this study provided a direction for identifying patients at risk for irAEs, and guiding patient selection for ICI therapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.987568","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T05:43:45Z","timestamp":1662615825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Serological biomarkers predict immune-related adverse events and clinical benefit in patients with advanced gastrointestinal 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