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

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. [Display omitted] •Intratumoral (IT) CXCL9/10-DC inhibits tumor growth in NSCLC murine models•IT CXCL9/10-DC induces T cell infiltration and activation inside the tumor•IT CXCL9/10-DC enhances the antitumor efficacy of immune checkpoint blockade•IT CXCL9/10-DC and anti-PD-1 combination leads to tumor-specific immune memory Lim et al. report intratumoral (IT) administration of chemokine genes CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a potential therapy for non-small cell lung cancer (NSCLC). IT CXCL9/10-DC promotes T cell infiltration and activation in the tumor microenvironment and enhances antitumor efficacy of immune checkpoint blockade in murine NSCLC models.