Biology subjects

Raffo-Iraolagoitia, X. L.

Publications and source records attributed to Raffo-Iraolagoitia, X. L..

4 recordsLinked to original sources

bioRxiv2024

Integrin inactivation slows down neutrophils congesting the pre-metastatic lung in a model of breast cancer

Neutrophils are thought to be critical to the process whereby breast cancers establish an immunosuppressive and tumour cell nurturing pre-metastatic niche before overt metastasis can be detected. However, the spatial localization of neutrophils and their interaction with other cell types in the lung pre-metastatic niche is not well described. We used a spontaneously metastatic mammary cancer model combined with a multiplexed three- and four-dimensional imaging approach to investigate the behaviour of neutrophils in the pre-metastatic niche. Volume fixed tissue three-dimensional imaging showed that approximately 40% of CD8+ T cells are adjacent to neutrophils at this stage. In live tissue, we found neutrophils with impaired intravascular motility congested the capillaries of pre-metastatic lungs potentially obstructing CD8+ T cells. Slowed neutrophil transit was dependent on the conformation of {beta}2-integrin and could be recapitulated by treating non-tumour bearing mice with G-CSF, a potent systemic mediator of granulopoiesis. We found a decrease in L-selectin (CD62L) on neutrophils in the lungs of both mammary tumour bearing and G-CSF treated mice. Finally, we observed differential accumulation of intravenously injected micro-beads in the lung, suggestive of transient circulatory dead spaces which were also dependent on {beta}2-integrin inactivation. Overall, our study proposes that integrin-mediated neutrophil congestion of the alveolar capillaries could contribute to the generation of the pulmonary pre-metastatic niche.

immunology↗

bioRxiv2023

γδ T cells impair airway macrophage differentiation in lung adenocarcinoma

Protecting mucosal barriers, {gamma}{delta} T cells hold promise for the development of new cancer immunotherapies. In mice, {gamma}{delta} T cells can largely be segregated into CD27+ and CD27- cells, and their functions are modulated by interactions with surrounding cells. However, which cells communicate directly with {gamma}{delta} T cells in lung adenocarcinoma remains unknown. To address this, we combined flow cytometry, confocal microscopy, and scRNA-seq, using an autochthonous genetically engineered mouse model and different {gamma}{delta} T cell-deficient settings. We found that {gamma}{delta} T cells were increased in tumour-bearing lungs, with an altered phenotype. CD27- and CD27+ {gamma}{delta} T cells differed in their localisation and interactions including their tropism for macrophages. Overall, we propose a model where CD27+ {gamma}{delta} T cells undermine the differentiation of tumour-associated macrophages into airway macrophages, fostering a negative outcome in lung adenocarcinoma. Determining its translatability to human health may offer new avenues for immunotherapeutic strategies. SummaryGuardians of pulmonary homeostasis, {gamma}{delta} T cells remain enigmatic regarding their role in lung adenocarcinoma. Raffo-Iraolagoitia et al. report that a subset of {gamma}{delta} T cells impairs the differentiation of tumour-associated macrophages into airway macrophages, relevant for the outcome of lung adenocarcinoma. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/557344v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@e679f7org.highwire.dtl.DTLVardef@15152dforg.highwire.dtl.DTLVardef@17eaa5org.highwire.dtl.DTLVardef@2e0e47_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Maturation, developmental site, and pathology dictate murine neutrophil function

Neutrophils have been implicated in poor outcomes in cancer and severe inflammation. We found that neutrophils expressing intermediate levels of Ly6G (Ly6GInt) were present in mouse cancer models and more abundant in those with high rates of spontaneous metastasis. Maturation, age, tissue localization and functional capacity all drive neutrophil heterogeneity. Recent studies have proposed various markers to distinguish between these heterogeneous sub-populations; however, these markers are limited to specific models of inflammation and cancer. Here, we identify and define Ly6G expression level as a robust and reliable marker to distinguish neutrophils at different stages of maturation. Ly6GInt neutrophils were bona fide immature neutrophils with reduced immune regulatory and adhesion capacity. Whereas the bone marrow is a more recognised site of granulopoiesis, the spleen also produces neutrophils in homeostasis and cancer. Strikingly, neutrophils matured faster in the spleen than in the bone marrow with unique transcriptional profiles. We propose that developmental origin is critical in neutrophil identity and postulate that neutrophils that develop in the spleen supplement the bone marrow by providing an intermediate more mature reserve before emergency haematopoiesis.

immunology↗

bioRxiv2020

Asbestos accelerates disease onset in a genetic model of Malignant Pleural Mesothelioma

HypothesisAsbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. MethodsGenetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. ResultsInjection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours initiated in the presence of asbestos showed increased macrophage infiltration. Single-agent suppression of macrophages in mice with established tumours failed to extend survival. ConclusionAsbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages alone in established disease showed no therapeutic benefit.

cancer biology↗