Following up biomarker data from patients with late-stage melanoma treated with intratumoral (i.t.) IL-12 DNA, which showed that increases in i.t. CXCR3 transcripts correlated with treatment responses, Lee et al. investigated whether electroporating a CXCL9 DNA plasmid could boost the efficacy of i.t. IL-12. In murine tumor models, localized IL-12 and CXCL9 treatment promoted dendritic cell antigen presentation and CD8+ T cell activation, resulting in a significant abscopal tumor response and improved anti-PD-1 responses. A functional CXCR3/CXCL9 axis was required for IL-12 efficacy, which increased and stimulated efficient trafficking of CD8+ cells into the TME.
Contributed by Katherine Turner
ABSTRACT: 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.