EML4-ALK Rearrangement Creates a Distinctive Myeloid Cell-Dominant Immunosuppressive Microenvironment in Lung Cancer

Tyrosine kinase inhibitors are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma, but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for tyrosine kinase inhibitor-resistant cases. Although the use of immune checkpoint inhibitors (ICI) has improved the prognosis of patients with lung cancer, patients with ALK+ lung adenocarcinoma exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. In this study, we explored the immunologic status of the tumor microenvironment (TME) in ALK+ lung adenocarcinoma tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSC) relative to ALK- lung adenocarcinoma cases, indicating that ALK+ lung adenocarcinoma 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+ lung adenocarcinoma. In contrast, ALK+ lung adenocarcinoma expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ lung adenocarcinoma showed higher levels of IL6, an MDSC-inducing cytokine, than ALK- lung adenocarcinoma. An IL6R inhibitor transformed the TME in a murine ALK+ lung adenocarcinoma model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL6R 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+ lung adenocarcinoma. See related Spotlight by Vitale and Bria, p.1326.