Tissue specific Cish expression supports alveolar macrophage homeostatic function

Macrophages play critical roles in defense against microbes and clearance of dead cells, but also perform tissue specific functions in homeostasis. Distinct gene expression signatures in macrophages isolated from varying tissues are largely determined by environmental signals. Specifically, the lung is highly susceptible to environmental changes, such as O2 pressure and inhalation of particulate and microbes. Alveolar macrophages are shaped by the lung environment and have critical tissue-specific functions in initiating and resolving lung inflammation, and in maintaining lung structure via surfactant and lipid catabolism. While research speculates lung specific factors form alveolar macrophage phenotype and homeostatic function, the specific signals and regulators remain largely unknown. Therefore, we sought to explore lung specific cytokine signals and downstream signaling regulators that shape homeostatic functions of alveolar macrophages. We found Cytokine Inducible SH2 Containing Protein (Cish), a SOCS family member known to regulate the JAK-STAT5 pathway, is basally expressed in a tissue-specific manner in alveolar macrophages. Further, we found that the STAT5 activating cytokine GM-CSF regulates Cish expression in alveolar macrophages and observed reduced alveolar macrophage Cish expression with GM-CSF blockade in the lung. Cish knockout mice exhibit enlarged “foamy” alveolar macrophages, impaired surfactant metabolism, and dysregulated response to GM-CSF, all hallmarks of pulmonary alveolar proteinosis. Thus, we show alveolar macrophage Cish expression is directly linked to lung specific factors, namely GM-CSF, and influences surfactant homeostasis in the lung, a critical homeostatic function of alveolar macrophages. The lung is an especially critical site of protection as it is a barrier site that is constantly exposed to inhaled particulate and microbes and possesses a fragile structure. Alveolar macrophages act as sentinels in the lung, protecting this sensitive tissue from challenge while maintaining proper homeostasis and structure. From a public health perspective, continuing to elucidate the specific mechanisms by which alveolar macrophages mediate lung homeostasis is essential to providing cutting edge health care and to continuing to develop therapeutic treatments that can provide cures instead of simply mitigating symptoms of pulmonary disease. Here, we highlight one of many yet to be uncovered regulators of lung homeostasis

Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas

Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns