Immunoprofiling bronchoalveolar lavage cells reveals multifaceted smoking-associated immune dysfunction.

Background: Bronchoalveolar lavage (BAL) is an underutilised tool in the search for pulmonary disease biomarkers. While leukocytes with effector and suppressor function play important roles in airway immunity and tumours, it remains unclear if frequencies and phenotypes of BAL leukocytes can be useful parameters in lung cancer studies and clinical trials. We therefore explored the utility of BAL leukocytes as a source of biomarkers interrogating the impact of smoking, a major lung cancer risk determinant, on pulmonary immunity. Methods: In this "test case" observational study, BAL samples from 119 donors undergoing lung cancer screening and biopsy procedures were evaluated by conventional and spectral flow cytometry to exemplify the comprehensive immune analyses possible with this biospecimen. Proportions of major leukocyte populations and phenotypic markers levels were found. Multivariate linear rank sum analysis considering age, sex, cancer diagnosis and smoking status was performed. Results: Significantly increased frequencies of myeloid-derived suppressor cells and PD-L1-expressing macrophages were found in current and former smokers compared to never-smokers. While cytotoxic CD8 T-cells and conventional CD4 helper T-cell frequencies were significantly reduced in current and former smokers, expression of immune checkpoints PD-1 and LAG-3 as well as Tregs proportions were increased. Lastly, the cellularity, viability and stability of several immune readouts under cryostorage suggested BAL samples are useful for correlative end-points in clinical trials. Conclusions: Smoking is associated with heightened markers of immune dysfunction, readily assayable in BAL, that may reflect a permissive environment for cancer development and progression in the airway.

Inhibiting the biogenesis of myeloid-derived suppressor cells enhances immunotherapy efficacy against mammary tumor progression.

While immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape in oncology, they are effective in select subsets of patients. Efficacy may be limited by tumor-driven immune suppression, of which 1 key mechanism is the development of myeloid-derived suppressor cells (MDSCs). A fundamental gap in MDSC therapeutics is the lack of approaches that target MDSC biogenesis. We hypothesized that targeting MDSC biogenesis would mitigate MDSC burden and bolster tumor responses to ICIs. We tested a class of agents, dihydroorotate dehydrogenase (DHODH) inhibitors, that have been previously shown to restore the terminal differentiation of leukemic myeloid progenitors. DHODH inhibitors have demonstrated preclinical safety and are under clinical study for hematologic malignancies. Using mouse models of mammary cancer that elicit robust MDSC responses, we demonstrated that the DHODH inhibitor brequinar (a) suppressed MDSC production from early-stage myeloid progenitors, which was accompanied by enhanced myeloid maturation; (b) augmented the antitumor and antimetastatic activities of programmed cell death 1-based (PD-1-based) ICI therapy in ICI-resistant mammary cancer models; and (c) acted in concert with PD-1 blockade through modulation of MDSC and CD8+ T cell responses. Moreover, brequinar facilitated myeloid maturation and inhibited immune-suppressive features in human bone marrow culture systems. These findings advance the concept of MDSC differentiation therapy in immuno-oncology.

Visceral Obesity Promotes Lung Cancer Progression-Toward Resolution of the Obesity Paradox in Lung Cancer.

INTRODUCTION: Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. METHODS: Hypothesizing that this "obesity paradox" arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. RESULTS: We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. CONCLUSIONS: In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.