Elias, Rawad

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease in which bulky tumor burden and limited time to develop antitumor T cells may have contributed to poor clinical efficacy. Here, we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti–PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. Experimental Design: We used single-cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. Results: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T-cell clonotypes observed in the tumor. Conclusions: Cytotoxic T cells in the blood of patients with PDAC remain sensitive to reinvigoration by PD-1 blockade, and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti–PD-1 reinvigoration and marks these T cells as non-productive contributors to antitumor immunity. See related commentary by Lander and DeNardo, p. 474

Abstract Background: The prevalence of electronic cigarette (e-cigarette) use and its impact on smoking cessation among cancer survivors in the United States is largely unknown. We sought to estimate the prevalence of e-cigarette use and examine its associations with cigarette smoking and smoking quit attempts among smoking-related cancer survivors in the United States. Methods: We obtained data from the 2014–2017 annual cycles of the National Health Interview Survey for participants with self-reported history of smoking-related cancer(s). We calculated the prevalence of current e-cigarette use and utilized multinomial logistic regression in examining the independent association between e-cigarette use and cigarette smoking. Appropriate survey weights were applied in estimating the prevalence rates, relative risk ratios (RRR), ORs, and confidence intervals (CI). Results: Our sample comprised 3,162 smoking-related cancer survivors. The prevalence of current e-cigarette use was 3.18% (95% CI, 2.40–3.96). Current e-cigarette users were 83 times as likely as never users to be current cigarette smokers (RRR, 82.89; 95% CI, 16.54–415.37). Among those with a history of cigarette smoking, current e-cigarette users were 90% less likely to be former smokers (OR, 0.10; 95% CI, 0.05–0.18). No association was seen between current e-cigarette use and a smoking quit attempt in the prior year. Conclusions: E-cigarette use among cigarette ever smokers was associated with a lower likelihood of being a former smoker/having quit smoking, and e-cigarette use was not associated with smoking quit attempts. Impact: Our findings do not provide evidence that e-cigarette use facilitates smoking cessation among smoking-related cancer survivors.