Oncogenic KRAS-dependent stromal interleukin-33 directs the pancreatic microenvironment to promote tumor growth.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here, we show that signals from epithelial cells expressing oncogenic KRAS -a hallmark pancreatic cancer mutation- activate fibroblast autocrine signaling, which drives expression of the cytokine interleukin-33 (IL-33). Stromal IL-33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces IL-33 secretion. Using compartment-specific IL-33 knockout mice, we observed that lack of stromal IL-33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells and lymphocytes. Notably, loss of stromal IL-33 leads to an increase in CD8+ T cell infiltration and activation, and, ultimately, reduced tumor growth.

Impact of lung cancer screening on stage migration and mortality among the national Veterans Health Administration population with lung cancer.

BACKGROUND: Despite randomized trials demonstrating a mortality benefit to low-dose computed tomography screening to detect lung cancer, uptake of lung cancer screening (LCS) has been slow, and the benefits of screening remain unclear in clinical practice. METHODS: This study aimed to assess the impact of screening among patients in the Veterans Health Administration (VA) health care system diagnosed with lung cancer between 2011 and 2018. Lung cancer stage at diagnosis, lung cancer-specific survival, and overall survival between patients with cancer who did and did not receive screening before diagnosis were evaluated. We used Cox regression modeling and inverse propensity weighting analyses with lead time bias adjustment to correlate LCS exposure with patient outcomes. RESULTS: Of 57,919 individuals diagnosed with lung cancer in the VA system between 2011 and 2018, 2167 (3.9%) underwent screening before diagnosis. Patients with screening had higher rates of stage I diagnoses (52% vs. 27%; p ≤ .0001) compared to those who had no screening. Screened patients had improved 5-year overall survival rates (50.2% vs. 27.9%) and 5-year lung cancer-specific survival (59.0% vs. 29.7%) compared to unscreened patients. Among screening-eligible patients who underwent National Comprehensive Cancer Network guideline-concordant treatment, screening resulted in substantial reductions in all-cause mortality (adjusted hazard ratio [aHR], 0.79; 95% confidence interval [CI], 0.67-0.92; p = .003) and lung-specific mortality (aHR, 0.61; 95% CI, 0.50-0.74; p < .001). CONCLUSIONS: While LCS uptake remains limited, screening was associated with earlier stage diagnoses and improved survival. This large national study corroborates the value of LCS in clinical practice; efforts to widely adopt this vital intervention are needed.