1. CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer
- Author
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Lim, Raymond J, Salehi-Rad, Ramin, Tran, Linh M, Oh, Michael S, Dumitras, Camelia, Crosson, William P, Li, Rui, Patel, Tejas S, Man, Samantha, Yean, Cara E, Abascal, Jensen, Huang, ZiLing, Ong, Stephanie L, Krysan, Kostyantyn, Dubinett, Steven M, and Liu, Bin
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Lung Cancer ,Lung ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Humans ,Mice ,Animals ,Lung Neoplasms ,CD8-Positive T-Lymphocytes ,Carcinoma ,Non-Small-Cell Lung ,Immune Checkpoint Inhibitors ,Dendritic Cells ,Tumor Microenvironment ,Chemokine CXCL9 ,CXCL10 ,CXCL9 ,CXCR3 ,NSCLC ,T cells ,checkpoint blockade ,dendritic cells ,immunosuppression ,in situ vaccination ,systemic immunity ,Biomedical and clinical sciences - Abstract
Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.
- Published
- 2024