CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer

  • Cell Rep Med. 2024 Apr 16;5(4):101479. doi: 10.1016/j.xcrm.2024.101479.
Raymond J Lim  1 ,  Ramin Salehi-Rad  2 ,  Linh M Tran  2 ,  Michael S Oh  3 ,  Camelia Dumitras  4 ,  William P Crosson  1 ,  Rui Li  5 ,  Tejas S Patel  4 ,  Samantha Man  4 ,  Cara E Yean  4 ,  Jensen Abascal  6 ,  ZiLing Huang  4 ,  Stephanie L Ong  4 ,  Kostyantyn Krysan  2 ,  Steven M Dubinett  7 ,  Bin Liu  8
Affiliations
  • 1. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
  • 3. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 4. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 5. Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 6. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 7. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
  • 8. Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
PMID: 38518770 DOI: 10.1016/j.xcrm.2024.101479
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.

Keywords
CXCL10; CXCL9; CXCR3; NSCLC; T cells; checkpoint blockade; dendritic cells; immunosuppression; in situ vaccination; systemic immunity.