The transcriptome of lung tumor-infiltrating dendritic cells reveals a tumor-supporting phenotype and a microRNA signature with negative impact on clinical outcome

Abstract

Targeting immunomodulatory pathways has ushered a new era in lung cancer therapy. Further progress requires deeper insights into the biology of immune cells in the lung cancer micro-environment.Dendritic cells (DCs) represent a heterogeneous and highly plastic immune cell system with a central role in controlling immune responses. The intratumoral infiltration and activation status of DCs are emerging as clinically relevant parameters in lung cancer.In this study, we used an orthotopic preclinical model of lung cancer to dissect how the lung tumor micro-environment affects tissue-resident DCs and extract novel biologically and clinically relevant information.Lung tumor-infiltrating leukocytes expressing generic DC markers were found to predominantly consist of CD11b+ cells that, compare with peritumoral lung DC counterparts, strongly overexpress the T-cell inhibitory molecule PD-L1 and acquire classical surface markers of tumor-associated macrophages (TAMs). Transcriptome analysis of these CD11b+ tumor-infiltrating DCs (TIDCs) indicates impaired antitumoral immunogenicity, confirms the skewing toward TAM-related features, and indicates exposure to a hypoxic environment. In parallel, TIDCs display a specific microRNA (miRNA) signature dominated by the prototypical lung cancer oncomir miR-31. In vitro, hypoxia drives intrinsic miR-31 expression in CD11b+ DCs. Conditioned medium of miR-31 overexpressing CD11b+ DCs induces pro-invasive lung cancer cell shape changes and is enriched with pro-metastatic soluble factors. Finally, analysis of TCGA datasets reveals that the TIDC-associated miRNA signature has a negative prognostic impact in non-small cell lung cancer.Together, these data suggest a novel mechanism through which the lung cancer micro-environment exploits the plasticity of the DC system to support tumoral progression.

Tissue‐resident innate immunity in the lung

“…129 CD103 + DCs alone appear to orchestrate the appropriate Th17 response to fungal infection through production of IL-2 and IL-23. 131,132 Cell-tracking experiments in murine melanoma tumour models show that CD103 + DCs are the only intra-tumoral myeloid cell type able to transport and present intact antigen to tumour-specific CD8 + T cells and their activation was protective against tumour re-challenge. DCs take up necrotic and apoptotic tumour fragments to present to antigen-specific cytotoxic and helper T cells, and are therefore important providers of protective anti-cancer immunity.…”

“…DCs take up necrotic and apoptotic tumour fragments to present to antigen-specific cytotoxic and helper T cells, and are therefore important providers of protective anti-cancer immunity. 130,131 The importance of DCs in lung cancer is demonstrated by ongoing efforts to harness these cells for therapeutic purposes. 133 However, these cells are rare and transcriptomic analysis of lung cancers and peritumoral tissues from mice demonstrate that the majority of infiltrating myeloid cells are actually CD11b + DCs.…”

“…DCs take up necrotic and apoptotic tumour fragments to present to antigen-specific cytotoxic and helper T cells, and are therefore important providers of protective anti-cancer immunity. 131,132 Cell-tracking experiments in murine melanoma tumour models show that CD103 + DCs are the only intra-tumoral myeloid cell type able to transport and present intact antigen to tumour-specific CD8 + T cells and their activation was protective against tumour re-challenge. 133 However, these cells are rare and transcriptomic analysis of lung cancers and peritumoral tissues from mice demonstrate that the majority of infiltrating myeloid cells are actually CD11b + DCs.…”

The role and therapeutic implications of T cells in cancer of the lung

“…19 In murine models adoptive transfer tumourspecific CTL leads to tumour eradication in WT mice, whereas transfer of CTL to CD40 deficient mice did not lead to an effective anti-tumour immune response. 22 Tertiary lymphoid structures (TLSs) or the local TDLN provides sites for tumor antigen crosspriming by DCs in an environment sheltered from tumor-derived inhibitory molecules and cytokines ( Figure 3). 21 Furthermore, other studies have indicated that lung tumor-infiltrating CD11b + DCs strongly overexpress PD-L1, contributing to immunosuppression and tumor growth.…”

“…studies have indicated that lung tumor-infiltrating CD11b + DCs strongly overexpress PD-L1, contributing to immunosuppression and tumor growth. 22 Tertiary lymphoid structures (TLSs) or the local TDLN provides sites for tumor antigen crosspriming by DCs in an environment sheltered from tumor-derived inhibitory molecules and cytokines ( Figure 3). 13 Recent research has indicated that TLSs are critical in shaping the antitumor immune response, favouring a Th1 cell phenotype.…”