EML4-ALK rearrangement creates a distinctive myeloid cell–dominant immunosuppressive microenvironment in lung cancer

Abstract Tyrosine kinase inhibitors (TKIs) are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene–positive lung adenocarcinoma (ALK+ LUAD), but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for TKI-resistant cases. Although the use of immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with lung cancer, patients with ALK+ LUAD exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. Here, we explored the immunological status of the tumor microenvironment (TME) in ALK+ LUAD tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSCs) relative to ALK– LUAD cases, indicating that ALK+ LUAD has a myeloid cell–dominant immunosuppressive TME. Single-cell RNA-sequencing analysis identified a subset of macrophages that expressed most T cell–attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ LUAD. In contrast, ALK+ LUAD expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ LUAD showed higher levels of IL-6, an MDSC-inducing cytokine, than ALK– LUAD. An IL-6R inhibitor transformed the TME in a murine ALK+ LUAD model, shifting it from an immunosuppressive to a T cell–dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL-6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene–mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ LUAD.