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.
Messenger RNA (mRNA) has become a promising tool in therapeutic cancer vaccine strategies. Owing to its flexible design and rapid production, mRNA is an attractive antigen delivery format for cancer vaccines targeting mutated peptides expressed in a tumor-the so-called neoantigens. These neoantigens are rarely shared between patients, and inclusion of these antigens in a vaccine requires the production of individual batches of patient-tailored mRNA. The authors have developed MIDRIX NEO , a personalized mRNA-loaded dendritic cell vaccine targeting tumor neoantigens, which is currently being evaluated in a phase 1 clinical study in lung cancer patients. To facilitate this study, the authors set up a Good Manufacturing Practice (GMP)-compliant production process for the manufacture of small batches of personalized neoantigenencoding mRNA. In this article, the authors describe the complete mRNA production process and the extensive quality assessment to which the mRNA is subjected. Validation runs have shown that the process delivers mRNA of reproducible, high quality. This process is now successfully applied for the production of neoantigen-encoding mRNA for the clinical evaluation of MIDRIX NEO . To the authors' knowledge, this is the first time that a GMP-based production process of patient-tailored neoantigen mRNA has been described.
Vandekerckhove (2020): Treatment of a patient with severe cytomegalovirus (CMV) infection after haploidentical stem cell transplantation with donor-derived CMV-specific T cells, Acta Clinica Belgica,
Tumor-derived micro-RNA expression patterns are known to convey prognostic information in lung cancer. However, the cellular source of these signatures is unclear. In parallel, immunological parameters such as the presence and activation status of dendritic cells (DCs) emerge as important prognostic factors in this disease as well, presumably by affecting the quality of immune surveillance.We hypothesized that tumor-associated DCs are involved in the way tumor-derived miRNA expression patterns impact on disease outcome.Using a preclinical model of lung cancer featuring orthotopic tumor growth in syngeneic, immunocompetent hosts, we found that lung tumors were preferentially infiltrated by CD11c+/MHCII+/CD11b+/CD103- DCs (TIDCs). Compared to their peritumoral counterparts, displayed a dramatic overexpression of PD-L1 along with markers associated with tumor-associated macrophages (TAM). Transcriptome analysis of these CD11b+ TIDCs vs peritumoral CD11b+ DCs using GSEA and ISMARA indicated loss of immunogenicity, upregulation of features related to immunosuppressive TAMs, and exposure to hypoxia. Global miRNA profiling of CD11b+TIDCs revealed a specific signature dominated by a strong overexpression of mir-31, a prototypical lung cancer oncomir. Exposure to hypoxia appeared as a powerful driver of endogenous miR-31 expression in DCs. Confocal microscopy of intrapulmonary tumors confirmed that CD11c+ dendritic-shaped leukocytes colocalize within hypoxic regions. We found that miR-31 overexpression and hypoxia alike cause DCs to secrete the tumor-supporting factors VEGF, S100A8 and S100A9. Conditioned medium of miR-31-overexpression DCs induced pro-invasive cell morphology changes in lung carcinoma cells cultured on a collagen matrix, a phenomenon that could be reproduced by exposure to recombinant S100A8 protein. By re-processing TCGA expression data for non-coding RNA sequences, we discovered that the lung TIDC miRNA signature imparts a strong negative impact on overall survival in non-squamous lung cancer. Moreover, the TIDC-derived miRNA signature induced a profound difference in outcome among lung cancer patients with regional lymph node invasion.In summary, lung tumors predominantly recruit inflammatory-type DCs that are reprogrammed at the level of immuno-phenotype and micro-RNA repertoire. The miRNA signature of lung tumor-infiltrating DCs is dominated by the miR-31, a hypoxia-induced oncomir stimulating the release of pro-metastatic proteins by DCs. Finally, we show for the first time that a miRNA signature derived from a stromal immune cell has a dramatic impact on long term outcome in lung cancer. Citation Format: Elisabeth Brabants, Lotte Pyfferoen, Celine Everaert, Simon Tavernier, Kelly Heyns, Nancy De Cabooter, Glenn Wagemans, Kim Deswarte, Hamida Hammad, Olivier De Wever, Jo Vandesompele, Bart Lambrecht, Pieter Mestdagh, Karim Vermaelen. Specific myelomonocytic cells heavily infiltrate orthotopic lung tumors and display a hypoxia-driven miRNA expression signature that directs tumor-supporting functions and negatively impacts on clinical outcome [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A091.
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