MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Abstract

Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3–transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3–induced protection from apoptosis. Altogether, our data suggest that the LAG-3–MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3–MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…For example, the interaction between LAG3, a surface molecule expressed on exhausted lymphocytes, and HLA class II antigens can enhance survival and apoptosis resistance of melanoma cells. 87 …”

Emerging immune checkpoints for cancer therapy

“…Expression of LAg-3 on T cells is associated with the downregulation of cytokine secretion [35,36], while LAg-3 induces the production of Th1 cytokine such as iL-2 in vitro [37], suggesting that LAg-3 may play a double role in regulating T-cell function. LAg-3-induced protection against the LAg-3-MHC ii interaction might be shared by tumor cells and immune cells [38], indicating the dual identity of LAg-3 in immune response to tumors.…”

“…Fas has been acknowledged as a critical pathway of immune-mediated killing of melanoma [38]. in a melanoma model, both sLAg-3 and LAg-3-transfected cells could prevent MHC ii-positive melanoma cells from Fas-mediated and/or druginduced apoptosis possibly via MAPK/Erk and Pi3K/Akt pathways.…”

“…And several subsets of LAg-3-expressing T cells are expanded in the peripheral blood of patients with advanced cancer [24,38,44]. As a soluble molecule, sLAg-3 activates APCs through MHC class ii signaling [51], leading to increased antigen-specific CD8  T-cell responses characterized by CTL activity and enhanced final antitumor immune response in vivo [32].…”

Antibody-Mediated Phosphatidylserine Blockade Enhances the Antitumor Responses to CTLA-4 and PD-1 Antibodies in Melanoma

“…14, 15), lymphocyte-activation gene 3 (LAG3; refs. 16,17), and Tim3 (18,19) and for agonists that activate immune stimulatory pathways, such as 4-1BB (CD-137; refs. 20, 21), OX40 (22,23), inducible T-cell costimulator (24), and GITR.…”