Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity.

Marco Donia,Rikke Andersen,Ferdinando Nicoletti,Mads Hald Andersen,Inge Marie Svane,Shamaila Munir,Julie W Kjeldsen,Per Thor Straten,Paolo Fagone

doi:10.1158/0008-5472.can-14-2956

Marco Donia, Rikke Andersen + Show 7 more

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https://doi.org/10.1158/0008-5472.can-14-2956

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Abstract

In the absence of a local inflammatory response, expression of MHC class II molecules is restricted mainly to hematopoietic cells and thymus epithelium. However, certain tumors, such as melanoma, may acquire aberrant constitutive expression of MHC class II. In a set of primary melanoma cell populations and correspondingly expanded autologous tumor-infiltrating lymphocytes (TIL), we show how MHC class II expression on melanoma cells associates with strong MHC class II-restricted CD4(+) T-cell responses that are specific for tumors. Notably, we found that tumor-specific CD4(+) T-cell responses were dominated by TNF production. TNF reduced CD8(+) T-cell activation in IFNγ-rich environments resembling a tumor site. Conversely, direct CD4(+) T-cell responses had no influence on either the proliferation or viability of melanoma cells. Taken together, our results illustrate a novel immune escape mechanism that can be activated by aberrant expression of MHC class II molecules, which by attracting tumor-specific CD4(+) T cells elicit a local inflammatory response dominated by TNF that, in turn, inhibits cytotoxic CD8(+) T-cell responses

Highlights

In the absence of a local inflammatory response, MHC class II expression is mainly restricted to hematopoietic cells and thymus epithelium [1,2,3]
When a minimum of 50 Â 106 tumor-infiltrating lymphocytes (TIL) were obtained, expansion was further achieved by a standard 14-days rapid expansion protocol (REP), in which TILs are unspecifically expanded with a 200-fold excess of allogeneic irradiated peripheral blood mononuclear cells (PBMC) from at least three different healthy donors, 30 ng/mL anti-CD3 antibodies (OKT3, from Janssen-Cilag or Miltenyi Biotec)
Despite the fact that in vivo tumor heterogeneity may not be fully reflected by short-term cultured autologous melanoma cell lines, coculture assays of TILs/autologous tumor cell lines currently represents a gold standard as they allow the identification of www.aacrjournals.org

Summary

Introduction

In the absence of a local inflammatory response, MHC class II expression is mainly restricted to hematopoietic cells and thymus epithelium [1,2,3]. Certain types of solid tumors, including a subset of melanomas, de novo constitutively express MHC class II molecules [1, 3]. MHC class II expression in melanoma has been previously associated with both shorter and longer survival [5,6,7]. MHC class II expression can make these tumors directly detectable by tumor-antigen-specific CD4þ T cells that we and others previously have shown to be capable of generating Th1 responses in response to autologous tumor antigens [8,9,10,11]. Recent studies proposed that engagement of MHC class II by lymphocyte-activation gene 3 (LAG3), expressed respectively on tumor cells and tumor-infiltrating immune cells, may trigger prosurvival signals and tumor cell resistance to apoptosis [12]. LAG3 has been characterized as an immune inhibitory receptor, and its engagement on T cells may mediate downregulation of immune responses in the tumor microenvironment during priming but not effector phase [13, 14]

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