Adaptive anti-tumor immunity is orchestrated by a population of CCL5-producing tissue-resident NK cells

Abstract

Targeting T cells for cancer immunotherapy commonly fails to generate lasting tumor control. Harnessing additional orchestrators of the immune response against tumors may enhance and broaden clinical benefit. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the amplification of anti-tumoral DC-T cell crosstalk by NK cells. Utilizing an engineered adenoviral platform for paracrine delivery into the tumor microenvironment, we show that IL-12 enhances functional DC-CD8 T cell interactions to generate profound anti-tumor immunity. This effect depends on the abundance of intra-tumoral NK cells and specifically their capacity to produce the DC chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade can be overcome by intra-tumoral therapeutic delivery of CCL5 resulting in the recruitment of cDC1s. Our findings reveal novel mechanistic insights how to enhance T cell-NK cell-DC crosstalks, enforcing a tumor-eliminating positive feedback mechanism to promote anti-tumor immunity and overcome resistance.

Single-cell transcriptomics reveals immunosuppressive microenvironment and highlights stumor-promoting macrophage cells in Glioblastoma

“…High expression of CXCR6 in NK cells within tumor tissues suggests multiple important roles in the TME, impacting immune cell interactions and potential therapeutic outcomes. Elevated levels of CXCR6 may enhance the efficacy of immunotherapies such as IL-12 and PD-1 blockade by promoting T cell-NK cell-dendritic cell cross-talk, essential for robust antitumor immunity [17]. This expression could reflect unique phenotypic and functional traits, including increased cytokine production and enhanced degranulation.…”

“…NK cells have a complex array of activating and inhibitory receptors. Within the TME, the balance tends to lean towards inhibition, either due to an abundance of ligands for inhibitory receptors on tumor cells or a lack of sufficient activating signals [17]. The TME contains various suppressive elements, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and immunosuppressive cytokines like TGF-β and IL-10.…”