Integrating scRNAseq, CODEX, and VISIUM data from esophageal squamous cell carcinoma patient tissues, Oyoshi and Du et al. substantiated increased immune cell infiltration into tumors, with dynamic changes in immunostimulatory and immunosuppressive gene expression during and following radiation therapy (RT), particularly among myeloid cells. A subgroup of myeloid cells with PD-L1 expression exhibited upregulation of coinhibitory and protumor genes, such as SIRPA, IDO1, CCL3, and IL-6, suggesting novel combinations with anti-PD-L1. Interestingly, some PD-L1+ myeloid cells also upregulated antitumor pathways.
Contributed by Shishir Pant
ABSTRACT: Radiotherapy (RT) combined with immunotherapy is promising; however, the immune response signature in the clinical setting after RT remains unclear. Here, by integrative spatial and single-cell analyses using multiplex immunostaining (CODEX), spatial transcriptome (VISIUM), and single-cell RNA sequencing, we substantiated the infiltration of immune cells into tumors with dynamic changes in immunostimulatory and immunosuppressive gene expression after RT. In addition, our comprehensive analysis uncovered time- and cell type-dependent alterations in the gene expression profile after RT. Furthermore, myeloid cells showed prominent up-regulation of immune response-associated genes after RT. Notably, a subset of infiltrating tumor-associated myeloid cells showing PD-L1 positivity exhibited significant up-regulation of immunostimulatory (HMGB1 and ISG15), immunosuppressive (SIRPA and IDO1), and protumor genes (CXCL8, CCL3, IL-6, and IL-1AB), which can be targets of immunotherapy in combination with PD-L1. These datasets will provide information on the RT-induced gene signature to seek an appropriate target for personalized immunotherapy combined with RT and guide the timing of combination therapy.
Author Info: (1) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (2) Division of Translational Informatics, Exploratory Oncology Research
Author Info: (1) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (2) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan. (3) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan. (4) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Division of Cancer Immunology, Research Institute/ Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan. (5) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (6) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (7) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (8) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (9) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (10) Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (11) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (12) Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (13) Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (14) Pathology Division, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. (15) Pathology Division, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. (16) Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan. (17) Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan. (18) Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8568, Japan. (19) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. (20) Division of Molecular Oncological Pharmacy, Faculty of Pharmacy, Keio University, Shibakouen, Minato-ku, Tokyo, 105-8512, Japan. (21) Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8562, Japan. (22) Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan. Division of Cancer Immunology, Research Institute/ Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277-8577, Japan. Division of Radiation Oncology and Particle Therapy, National Cancer Center Hospital East, Kashiwa, Chiba 277-8577, Japan.
