Arai et al. demonstrated that the EML4-ALK fusion gene created a myeloid cell-driven immunosuppressive TME. Fusion+ lung adenocarcinomas showed decreases in CXCL9, CXCL10, and CXCL11 T cell chemoattractants, and reduced T cell activation and adaptive immune response. ALK signaling through activation of the RAS/MAPK/AP-1 pathway upregulated CXCL1, CXCL8, and IL-6 expression, enhancing MDSC recruitment and induction, and M2 macrophage polarization. IL-6R blockade restored IFNγ production, reduced MDSC frequency, and enhanced anti-PD-L1 therapy in the ALK+ 3LL lung adenocarcinoma model.
Contributed by Shishir Pant
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.
Author Info: (1) National Cancer Center Research Institute, Tokyo, Japan. (2) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (3) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa
Author Info: (1) National Cancer Center Research Institute, Tokyo, Japan. (2) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (3) Chugai Pharmaceutical Co., Ltd., Yokohama, Kanagawa, Japan. (4) National Cancer Center Research Institute, Tokyo, Japan. (5) National Cancer Center Research Institute, Tokyo, Japan. (6) National Cancer Center Research Institute, Tokyo, Japan. (7) National Cancer Center Research Institute, Tokyo, Tokyo, Japan. (8) National Cancer Center Research Institute, Tokyo, Japan. (9) Chugai Pharmaceutical Co., Ltd., Yokohama City, Japan. (10) Chugai Pharmaceutical Co. Ltd., Yokohama, Kanagawa, Japan. (11) Roche (Switzerland), Basel, Basel-stadt, Switzerland. (12) Tokyo Women's Medical University, Tokyo, Japan. (13) Japanese Foundation For Cancer Research, Koto-ku, Tokyo, Japan. (14) National Cancer Center Research Institute, Tokyo, Tokyo, Japan. (15) National Cancer Center Hospital East, Chuo-ku, Tokyo, Japan. (16) National Cancer Center Hospital East, Tokyo, Japan. (17) National Cancer Center Research Institute, Tokyo, Chuo-ku, Japan. (18) The Cancer Institute Hospital of JFCR, Koto-ku, Tokyo, Japan. (19) Japanese Foundation For Cancer Research, Koto-ku, Tokyo, Japan. (20) Tokyo Medical and Dental University, Tokyo, Japan. (21) National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. (22) National Center for Geriatrics and Gerontology, Obu, Japan. (23) National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. (24) Keio University, Tokyo, Japan. (25) Keio University, Tsuruoka, Yamagata, Japan. (26) Keio University, Tsuruoka, Yamagata, Japan. (27) National Cancer Center Hospital East, Chuo-ku, Tokyo, Japan. (28) National Center for Global Health and Medicine, Japan. (29) Tokyo University of Science, Noda, Chiba, Japan. (30) Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. (31) National Cancer Center Research Institute, Tokyo, Tokyo, Japan.
