MHC Class I Loss Is a Frequent Mechanism of Immune Escape in Papillary Thyroid Cancer That Is Reversed by Interferon and Selumetinib TreatmentIn Vitro

Abstract

Purpose To evaluate Major Histocompatibility Complex (MHC) Class I expression on papillary thyroid cancer (PTC) and analyze changes in MHC expression and associated immune activation with current and experimental treatments for thyroid cancer using in vitro PTC cell lines. Experimental Design MHC Class I expression and assessment of tumor infiltrating leukocyte populations were evaluated by immunohistochemistry. PTC cell lines were analyzed for HLA-ABC expression by flow cytometry following tyrosine kinase inhibitor, interferon (IFN)-α or IFN-γ, or radiation treatment. Functional changes in antigenicity were assessed by co-culture of allogeneic donor peripheral blood leukocytes (PBL) with pre-treated or untreated PTC cell lines and measurement of T cell activation and cytokine production. Results Both MHC Class I and β2 microglobulin expression was reduced or absent in 76% of PTC specimens and was associated with reduced tumor infiltrating immune cells, including effector (CD3+, CD8+, CD16+) and suppressor (FoxP3+) populations. Treatment of PTC cell lines with the MEK1/2 inhibitor selumetinib or IFN increased HLA-ABC expression. This phenotypic change was associated with increased T cell activation (%CD25+ of CD3+) and interleukin 2 production by PBL co-cultured with treated PTC cell lines. Additive effects were seen with combination selumetinib and interferon treatment. Conclusions MHC Class I expression loss is frequent in human PTC specimens and represents a significant mechanism of immune escape. Increased antigenicity following selumetinib and IFN treatment warrants further study for immunotherapy of progressive PTC.

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