The expression “immunogenic cell death” (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as “damage-associated molecular patterns”. Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1386829

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.

In-depth knowledge of cancer molecular and cellular mechanisms have revealed a strong regulation of cancer development and progression by the inflammation which orchestrates the tumor microenvironment. Immune cells, residents or recruited, in the inflammation milieu can have rather contrasting effects during cancer development. Accumulated clinical and experimental data support the notion that acute inflammation could exert an immunoprotective effect leading to tumor eradication. However, chronic immune response promotes tumor growth and invasion. These reactions are mediated by soluble mediators or cytokines produced by either host immune cells or tumor cells themselves. Herein, we provide an overview of the current understanding of the role of the best-validated cytokines involved in tumor progression, IL-1, IL-4 and IL-6; in addition to IL-2 cytokines family, which is known to promote tumor eradication by immune cells. Furthermore, we summarize the clinical attempts to block or bolster the effect of these tumor-related interleukins in anti-cancer therapy development.

/pdf/tumor-related-interleukins-old-validated-targets-for-new-25k5cva9id.pdf

Tumor-related interleukins: old validated targets for new anti-cancer drug development

The functions and transcriptional profiles of dendritic cells (DCs) result from the interplay between ontogeny and tissue imprinting. How tumors shape human DCs is unknown. Here we used RNA-based next-generation sequencing to systematically analyze the transcriptomes of plasmacytoid pre-DCs (pDCs), cell populations enriched for type 1 conventional DCs (cDC1s), type 2 conventional DCs (cDC2s), CD14+ DCs and monocytes-macrophages from human primary luminal breast cancer (LBC) and triple-negative breast cancer (TNBC). By comparing tumor tissue with non-invaded tissue from the same patient, we found that 85% of the genes upregulated in DCs in LBC were specific to each DC subset. However, all DC subsets in TNBC commonly showed enrichment for the interferon pathway, but those in LBC did not. Finally, we defined transcriptional signatures specific for tumor DC subsets with a prognostic effect on their respective breast-cancer subtype. We conclude that the adjustment of DCs to the tumor microenvironment is subset specific and can be used to predict disease outcome. Our work also provides a resource for the identification of potential targets and biomarkers that might improve antitumor therapies.

Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific.

Dendritic- cells (DCs) have received considerable attention as potential targets for the development of anticancer vaccines. DC-based anticancer vaccination relies on patient-derived DCs pulsed with a source of tumor-associated antigens (TAAs) in the context of standardized maturation-cocktails, followed by their reinfusion. Extensive evidence has confirmed that DC-based vaccines can generate TAA-specific, cytotoxic T cells. Nonetheless, clinical efficacy of DC-based vaccines remains suboptimal, reflecting the widespread immunosuppression within tumors. Thus, clinical interest is being refocused on DC-based vaccines as combinatorial partners for T cell-targeting immunotherapies. Here, we summarize the most recent preclinical/clinical development of anticancer DC vaccination and discuss future perspectives for DC-based vaccines in immuno-oncology.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2019.1638212

Trial Watch: Dendritic Cell Vaccination for Cancer Immunotherapy

Objectives In non-small cell lung cancer (NSCLC), the immune system and possibly its composition affect survival. In this in silico study, the immune infiltrate composition in NSCLC patients was evaluated. Methods Gene expression data of tumors from early NSCLC patients were obtained from Gene Expression Omnibus (GEO). With CIBERSORT, 22 immune cell fractions were estimated. Results The immune infiltrate of 1430 pretreatment NSCLC patients contained mostly plasma cells, macrophages and CD8 T cells. Higher fractions of resting mast and CD4 T-helper cells were associated with longer overall survival (OS) (HR = 0.95, P < 0.01; HR = 0.98, = 0.04, respectively) and higher fractions of M2 macrophages and active dendritic cells with shorter survival (HR = 1.02, P = 0.03; HR = 1.03, P = 0.05, respectively). Adenocarcinoma patients with survival data (n = 587) showed higher fractions of resting mast and resting CD4 T cells, and lower M0 macrophages than squamous cell carcinoma (n = 254), which were associated with OS (HR = 0.95, P = 0.04; HR = 0.97, P = 0.01; HR = 1.03, P = 0.01, respectively). Fractions of memory B cells, naive CD4 T cells and neutrophils had different associations with survival depending on the subtype. Smokers had had higher fractions of regulatory T cell, follicular helper T cell, neutrophil and M2 macrophage, which were associated with shorter survival (HR = 1.3, P < 0.01; HR = 1.13, P = 0.02; HR = 1.09, P = 0.03; HR = 1.04, P = 0.02, respectively). Conclusion Pretreatment differences in immune cell composition in NSCLC are associated with survival and depend on smoking status and histological subtype. Smokers' immune composition is associated with lower survival.

/pdf/immune-microenvironment-composition-in-non-small-cell-lung-h7fz9xtqn7.pdf

Immune microenvironment composition in non-small cell lung cancer and its association with survival.

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.

https://tandfonline.com/doi/pdf/10.1080/2162402X.2016.1253655

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

An accelerated, clinical-grade protocol to generate high yields of type 1-polarizing messenger RNA-loaded dendritic cells for cancer vaccination.

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.

Abstract A091: 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

Elisabeth Brabants

Papers

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

An accelerated, clinical-grade protocol to generate high yields of type 1-polarizing messenger RNA-loaded dendritic cells for cancer vaccination.

Abstract A091: 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