Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, only a fraction of patients respond to ICB therapy. Accurate prediction of patients to likely respond to ICB would maximize the efficacy of ICB therapy. The tumor microenvironment (TME) dictates tumor progression and therapy outcome. Here, we classify the TME by analyzing the transcriptome from 11,069 cancer patients based on angiogenesis and T cell activity. We find three distinct angio-immune TME subtypes conserved across 30 non-hematological cancers. There is a clear inverse relationship between angiogenesis and anti-tumor immunity in TME. Remarkably, patients displaying TME with low angiogenesis with strong anti-tumor immunity show the most significant responses to ICB therapy in four cancer types. Re-evaluation of the renal cell carcinoma clinical trials provides compelling evidence that the baseline angio-immune state is robustly predictive of ICB responses. This study offers a rationale for incorporating baseline angio-immune scores for future ICB treatment strategies

Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis.

Extramedullary hematopoiesis (EMH) expands hematopoietic capacity outside of the bone marrow in response to inflammatory conditions, including infections and cancer. Because of its inducible nature, EMH offers a unique opportunity to study the interaction between hematopoietic stem and progenitor cells (HSPCs) and their niche. In cancer patients, the spleen frequently serves as an EMH organ and provides myeloid cells that may worsen pathology. Here, we examined the relationship between HSPCs and their splenic niche in EMH in a mouse breast cancer model. We identify tumor produced IL-1α and leukemia inhibitory factor (LIF) acting on splenic HSPCs and splenic niche cells, respectively. IL-1α induced TNFα expression in splenic HSPCs, which then activated splenic niche activity, while LIF induced proliferation of splenic niche cells. IL-1α and LIF display cooperative effects in activating EMH and are both up-regulated in some human cancers. Together, these data expand avenues for developing niche-directed therapies and further exploring EMH accompanying inflammatory pathologies like cancer

Tumor-derived Interleukin-1α and Leukemia Inhibitory Factor promote extramedullary hematopoiesis

This dataset contains raw data supporting all figures and supplemental figures, except for single cell RNA sequencing data and serum cytokine profiling data, used in PLOS Biology paper, Tumor-derived interleukin-1α and leukemia inhibitory factor promote extramedullary hematopoiesis (DOI: https://doi.org/10.1371/journal.pbio.3001746). This dataset includes 31 folders organized by Figure number and description of data type (flow cytometry, RT qPCR, ELISA, Immunofluorescence) and each folder contains a data dictionary file to describe variables

Priming of the respiratory tract with immunobiotic Lactobacillus plantarum limits infection of alveolar macrophages with recombinant pneumonia virus of mice (rK2-PVM)

Pneumonia virus of mice (PVM) is a natural rodent pathogen that replicates in bronchial epithelial cells and reproduces many clinical and pathological features of the more severe forms of disease associated with human respiratory syncytial virus. In order to track virus-target cell interactions during acute infection in vivo, we developed rK2-PVM, bacterial artificial chromosome-based recombinant PVM strain J3666 that incorporates the fluorescent tag monomeric Katushka 2 (mKATE2). The rK2-PVM pathogen promotes lethal infection in BALB/c mice and elicits characteristic cytokine production and leukocyte recruitment to the lung parenchyma. Using recombinant virus, we demonstrate for the first time PVM infection of both dendritic cells (DCs; CD11c(+) major histocompatibility complex class II(+)) and alveolar macrophages (AMs; CD11c(+) sialic acid-binding immunoglobulin-like lectin F(+)) in vivo and likewise detect mKATE2(+) DCs in mediastinal lymph nodes from infected mice. AMs support both active virus replication and production of infectious virions. Furthermore, we report that priming of the respiratory tract with immunobiotic Lactobacillus plantarum, a regimen that results in protection against the lethal inflammatory sequelae of acute respiratory virus infection, resulted in differential recruitment of neutrophils, DCs, and lymphocytes to the lungs in response to rK2-PVM and a reduction from ∼40% to <10% mKATE2(+) AMs in association with a 2-log drop in the release of infectious virions. In contrast, AMs from L. plantarum-primed mice challenged with virus ex vivo exhibited no differential susceptibility to rK2-PVM. Although the mechanisms underlying Lactobacillus-mediated viral suppression remain to be fully elucidated, this study provides insight into the cellular basis of this response. IMPORTANCE Pneumonia virus of mice (PVM) is a natural mouse pathogen that serves as a model for severe human respiratory syncytial virus disease. We have developed a fully functional recombinant PVM strain with a fluorescent reporter protein (rK2-PVM) that permits us to track infection of target cells in vivo. With rK2-PVM, we demonstrate infection of leukocytes in the lung, notably, dendritic cells and alveolar macrophages. Alveolar macrophages undergo productive infection and release infectious virions. We have shown previously that administration of immunobiotic Lactobacillus directly to the respiratory mucosa protects mice from the lethal sequelae of PVM infection in association with profound suppression of the virus-induced inflammatory response. We show here that Lactobacillus administration also limits infection of leukocytes in vivo and results in diminished release of infectious virions from alveolar macrophages. This is the first study to provide insight into the cellular basis of the antiviral impact of immunobiotic L. plantarum