Association of c-Myc and Immune Cell Infiltration in Small Cell Lung Carcinoma

Small cell lung carcinoma (SCLC) is a highly aggressive, rapidly proliferating malignancy largely corresponding to immune-cold tumor type. The role of the key oncogene c-Myc in regulating the complex immune microenvironment of SCLC remains unknown.

Immunohistochemistry and multiplex immunofluorescence techniques were used to analyze c-Myc expression and immune cell infiltration. c-Myc and β-catenin expression were analyzed using western blotting. Flow cytometry was used to quantify the expression of immunosuppressive ligands-including programmed death ligand 1 (PD-L1), CD47, CD155, and human leukocyte antigen-E (HLA-E)-and characterize the function of T cells and macrophages. Cytokine levels were evaluated using enzyme-linked immunosorbent assays.

c-Myc expression in high tumor-infiltrating lymphocyte infiltration (TIL^high) tumor exceeded that in TIL^low tumors (n = 24) and was positively correlated with CD163⁺ macrophage infiltration (p = 0.0180). Immunosuppressive ligands were universally expressed on SCLC cells. 10058-F4-a c-Myc inhibitor-substantially downregulated the expression of PD-L1, CD47, and CD155 and upregulated HLA-E expression. In the coculture system, the inhibition of c-Myc in SCLC cells significantly upregulated interferon-gamma production in Jurkat cells, inhibited macrophage phagocytosis, and decreased cytokine concentrations in the supernatant. Further mechanistic studies revealed that c-Myc inhibition modulated the Notch signaling pathway and reduced the expression of E-cadherin, vascular endothelial (VE)-cadherin, and β-catenin. A β-catenin agonist improved the regulatory effect of 10058-F4 on the immunosuppressive ligands in SCLC cells.

c-Myc expression in SCLC is associated with immune infiltration and may regulate the expression of immune-related ligands on SCLC cells via WNT/β-catenin signaling.