Using RNAseq, Gong et al. identified secreted PD-L1 (sPD-L1) splicing variants lacking the transmembrane domain in NSCLC patients who relapsed after anti-PD-L1 treatment. Patients with these variants had elevated levels of soluble PD-L1 in the plasma and in pleural effusion fluid. sPD-L1 variants conferred resistance to anti-PD-L1 in mice bearing MC38 tumors by accumulating soluble PD-L1 in the plasma, which could trap anti-PD-L1 and inhibit its function, thus shortening survival. Anti-PD-1 blockade efficacy was not affected by soluble PD-L1, and may be an option for patients with sPD-L1 variants.
Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non-small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti-PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys" of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti-PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.
Author Info: (1) Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science
Author Info: (1) Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. (2) Immunopharmacogenomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan. (3) Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. (4) Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (5) Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (6) Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. (7) INSERM U981, Gustave Roussy Cancer Campus, Universite Paris Saclay, Villejuif, France. Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France. (8) The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. (9) INSERM U981, Gustave Roussy Cancer Campus, Universite Paris Saclay, Villejuif, France. (10) The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. (11) Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. (12) Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan. (13) Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan. (14) Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan ryohei.katayama@jfcr.or.jp.
