Biology subjects

Cords, L.

Publications and source records attributed to Cords, L..

3 recordsLinked to original sources

bioRxiv2022

A Cancer-Associated Fibroblast Classification Framework for Single-Cell Data

Cancer-associated fibroblasts (CAFs) are a diverse cell population within the tumour microenvironment, where they have critical effects on tumour evolution and patient prognosis. To define CAF phenotypes, we analysed a single-cell RNA sequencing (scRNA-seq) dataset of over 16,000 stromal cells from tumours of 14 breast cancer patients, based on which we defined and functionally annotated nine CAF phenotypes and one class of pericytes. We validated this classification system in four additional cancer types and used highly multiplexed imaging mass cytometry on matched breast cancer samples to confirm our defined CAF phenotypes at the protein level and to analyse their spatial distribution within tumours. This general CAF classification scheme will allow comparison of CAF phenotypes across studies, facilitate analysis of their functional roles, and potentially guide development of new treatment strategies in the future.

cancer biology↗

bioRxiv2022

Acquired resistance to anti-PD1 therapy in patients with NSCLC reveals changes in T cell phenotypes and MET amplification

The treatment of non-small cell lung cancer (NSCLC) patients with immune checkpoint inhibitors has prolonged their survival dramatically. However, some patients develop resistance after initial response. Here, we used imaging mass cytometry and whole exome and RNA sequencing to analyze matching tumor samples from a cohort of NSCLC patients who initially responded to immune checkpoint inhibitor therapy and later developed acquired resistance. We detected two patterns of resistance: One group of patients had reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group showed high CD8+ T cell infiltration and high expression of PD-L1 and markedly elevated expression of other immune-inhibitory molecules. In two cases, we detected downregulation of type I and II IFN pathways after resistance developed, which could lead to an impaired anti-tumor immune response. This study adds to our knowledge of the mechanisms that cause resistance to immunotherapy in NSCLC patients.

cancer biology↗

bioRxiv2019

Missing-In-Metastasis / Metastasis Suppressor 1 modulates B cell receptor signaling, B cell metabolic potential and T cell-independent immune responses.

Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCR), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM-/- B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG. In vivo, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes which may also contribute to the poorly understood functions of MIM in cancer.

immunology↗