Amplification of the CXCR3/CXCL9 axis via intratumoral electroporation of plasmid CXCL9 synergizes with plasmid IL-12 therapy to elicit robust anti-tumor immunity.

Journal Article (Journal Article)

Clinical studies have demonstrated that local expression of the cytokine IL-12 drives interferon-gamma expression and recruits T cells to the tumor microenvironment, ultimately yielding durable systemic T cell responses. Interrogation of longitudinal biomarker data from our late-stage melanoma trials identified a significant on-treatment increase of intratumoral CXCR3 transcripts that was restricted to responding patients, underscoring the clinical relevance of tumor-infiltrating CXCR3+ immune cells. In this study, we sought to understand if the addition of DNA-encodable CXCL9 could augment the anti-tumor immune responses driven by intratumoral IL-12. We show that localized IL-12 and CXCL9 treatment reshapes the tumor microenvironment to promote dendritic cell licensing and CD8+ T cell activation. Additionally, this combination treatment results in a significant abscopal anti-tumor response and provides a concomitant benefit to anti-PD-1 therapies. Collectively, these data demonstrate that a functional tumoral CXCR3/CXCL9 axis is critical for IL-12 anti-tumor efficacy. Furthermore, restoring or amplifying the CXCL9 gradient in the tumors via intratumoral electroporation of plasmid CXCL9 can not only result in efficient trafficking of cytotoxic CD8+ T cells into the tumor but can also reshape the microenvironment to promote systemic immune response.

Full Text

Duke Authors

Cited Authors

  • Lee, JY; Nguyen, B; Mukhopadhyay, A; Han, M; Zhang, J; Gujar, R; Salazar, J; Hermiz, R; Svenson, L; Browning, E; Lyerly, HK; Canton, DA; Fisher, D; Daud, A; Algazi, A; Skitzki, J; Twitty, CG

Published Date

  • June 16, 2022

Published In

Volume / Issue

  • 25 /

Start / End Page

  • 174 - 188

PubMed ID

  • 35592387

Pubmed Central ID

  • PMC9092072

International Standard Serial Number (ISSN)

  • 2372-7705

Digital Object Identifier (DOI)

  • 10.1016/j.omto.2022.04.005

Language

  • eng

Conference Location

  • United States