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. Epub 2024 Mar 21.

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.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Non-Small-Cell Lung*
  • Chemokine CXCL9
  • Dendritic Cells
  • Humans
  • Immune Checkpoint Inhibitors
  • Lung Neoplasms*
  • Mice
  • Tumor Microenvironment

Substances

  • Immune Checkpoint Inhibitors
  • CXCL9 protein, human
  • Chemokine CXCL9