Prognostic significance of lymphocyte-activation gene-3 expression in chemoradiotherapy-naïve esophageal and gastric adenocarcinoma

• Background: Neoadjuvant and/or adjuvant treatment has led to an improved survival in patients with resectable gastroesophageal adenocarcinoma (GEAC). Nevertheless, survival rates remain poor and, hence, there is a great need to identify novel treatment strategies and relevant complementary diagnostics. Immunotherapies targeting the PD‐1/PD‐L1 checkpoints have shown promising results, but simultaneous inhibition of other fundamental checkpoints, such as lymphocyte-activation gene-3 (LAG‐3), may further improve clinical outcome. The expression and prognostic significance of LAG-3 in GEAC has however not yet been described. Herein, we examined the expression of LAG-3 in tumour-infiltrating immune cells (TIC) in chemoradiotherapy-naïve GEAC and paired lymph node metastases, with particular reference to its relationship with PD-1 and PD-L1 expression, mismatch repair (MMR) status, and survival. Methods: Immunohistochemical LAG-3 expression was analysed in tissue microarrays with 165 primary tumours and 72 paired lymph node metastases from a retrospective consecutive cohort of patients with chemoradiotherapy-naïve resected GEAC. LAG-3 expression was denoted in categories of negative (0), low (1-10) and high (>10). PD-1, PD-L1 expression and MMR status had been previously analysed. Results: The distribution of LAG-3 expression in primary tumours was 55.8% negative, 28.5% low, and 15.8% high. The corresponding figures in lymph node metastases were 48.6% negative, 37.5% low, and 13.9% high. LAG-3 expression did not differ by tumour location. Positive LAG-3 expression in primary tumours was an independent factor for prolonged overall survival in the entire cohort (HR = 0.64, 95% CI 0.43-0.96), and in gastric cancer (HR = 0.35, 95% CI 0.17-0.74). LAG-3 expression in primary tumours was significantly associated with PD-L1 expression in both tumour cells and TIC, and with PD-1 expression in TIC, but not with MMR status. Conclusions: LAG-3 is expressed in a considerable proportion of GEAC, with a similar distribution in primary tumours and lymph node metastases. Positive LAG-3 expression is an independent favourable prognostic factor, particularly in gastric cancer.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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