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ID: 658 (Conflict of Interest: K)

LAG3-Expression in tumorinfiltrierenden Lymphozyten (TILs) des Adenokarzinom des Ösophagus und Korrelation mit anderen vermeintlichen Tumor-Escape Mechanismen (MHC1, MHC2 und T-Zell-Entzündung)

M.Bagheri, H.Löser, M.Krämer, H.Fuchs, M.Bludau, W.Schröder, C. J.Bruns, F.Gebauer
Uniklinik Köln, Köln

Einleitung

MHC1 loss and MHC2 expression on carcinoma cells as well as LAG3 expression on regulatory T-cells are designated to contribute to an immunosuppressive tumor microenvironment. Phase-II studies have been initiated to investigate the effect of LAG3-inhibitors alone or in combination with a PD-1 blockade. However nothing is known about the frequency and impact of LAG3 expression and correlation with MHC1, MHC2 and T-cell inflammation in esophageal adenocarcinoma (EAC).

Material und Methoden

According to the suggestions of the international immunooncology working group for assessing TILs we created a multi spot tissue micro array with up to 12 tumor spots consider tumors of 165 patients as a test-cohort. To verify these results we created a single spot TMA consider 455 additional patients as a validation-cohort (620 patients in total). The Lag3 expression on TILs was assessed using immunohistochemistry (IHC) and mRNA by RNA-Scope in-situ technology. Furthermore we analyzed the expression data for MHC1, MHC2, CD3 and CD8 by IHC. These data were statistically correlated with survival and molecular data like TP53mutational status.

Ergebnisse

Patients with LAG3 protein-expression (13.4%) on TILs showed an improved overall-survival compared to patients without LAG3 expression (p = 0.046). There is a strong correlation between protein expression (IHC) and mRNA expression (p< 0.0001). Subgroup analysis revealed the survival difference in only those patients with TP53 mutations emphasizing a correlation of genetic aberrations and signs of immune activation measured by LAG3 expression. Advanced tumor stages (>pT2) showed a stronger LAG3-associated survival difference than early tumor stages. Loss of MHC1 on tumor cells was seen in 27.5%. Aberrant MHC2 expression on carcinoma cells was seen in 20.5% and was correlated with LAG3 overexpression (p < 0.001). CD3 expression is associated with significant better outcome in our cohort.

Schlussfolgerung

In our large cohort of EAC expression of LAG3 indicates favorable outcomes – fully in keeping with results described in breast cancer, but discrepant to other malignancies - showing the importance of immunomodulation in EAC during tumor progression. Our data suggest an impact of LAG3 and MHC2 on anti-tumoral T-cell effector function in EAC, however, it is likely that LAG3 overexpression alone does not predict whether a tumor will respond to LAG3 inhibition or not as we learned from PD-L1 expression.