Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer.

OBJECTIVES: Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. METHODS: We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. RESULTS: Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre-existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin-resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin-resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. CONCLUSIONS: Our clinically relevant and usable models reveal a key role for non-genetic factors in the evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell-intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum-resistant HGSC.

Up for Mischief? IL-17/Th17 in the tumour microenvironment.

The role of interleukin (IL)-17 and the IL-17-producing T helper (Th)17 cells in cancer has recently become the focus of extensive investigation. An expanding body of literature implicates Th17 cells and their hallmark cytokine in both pro- and anti-tumourigenic processes. In this review we describe their biological activities and outline the reciprocal interactions between Th17 cells and other cells of the immune system. We also discuss the evidence regarding their dual role in the tumour microenvironment. An understanding of the processes that regulate the pro- or anti-tumour activities of Th17 cell and IL-17 will allow the development of more effective means for cancer immunotherapy.

Control of apoptosis in autoimmunity.

Apoptosis and the subsequent removal of apoptotic cells underpin a healthy immune system. They are crucial for both the maintenance of self-tolerance and the contraction of clonally expanded lymphocytes at the conclusion of immune responses. Aberrant apoptosis and the disposal of apoptotic cells is implicated in the development of both systemic and organ-specific autoimmune disease and is a major contributing factor in disease susceptibility. Dissection of the molecular mechanisms involved in dysregulated apoptosis may reveal pathways which can be targeted for more effective therapeutic intervention. This review highlights the molecular events underlying programmed cell death and apoptotic cell uptake, and summarizes recent studies that link impaired apoptotic death to autoimmunity.

A neural-network approach to nonparametric and robust classification procedures.

In this paper algorithms of neural-network type are introduced for solving estimation and classification problems when assumptions about independence, Gaussianity, and stationarity of the observation samples are no longer valid. Specifically, the asymptotic normality of several nonparametric classification tests is demonstrated and their implementation using a neural-network approach is presented. Initially, the neural nets train themselves via learning samples for nominal noise and alternative hypotheses distributions resulting in near optimum performance in a particular stochastic environment. In other than the nominal environments, however, high efficiency is maintained by adapting the optimum nonlinearities to changing conditions during operation via parallel networks, without disturbing the classification process. Furthermore, the superiority in performance of the proposed networks over more traditional neural nets is demonstrated in an application involving pattern recognition.