SUMMARY Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically-engineered mouse lung adenocarcinoma model and found Treg cells suppress anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLS). TA-TLS have been described in human lung cancers, but their function remains to be determined. TLS in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLS upon Treg cell depletion, leading to tumor destruction. Thus, we propose Treg cells in TA-TLS can inhibit endogenous immune responses against tumors, and targeting these cells may provide therapeutic benefit for cancer patients.

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BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.small-cell lung cancer | targeted therapies | BH3 mimetics | apoptosis | BIM

BackgroundMobile apps hold promise for serving as a lifestyle intervention in public health to promote wellness and attenuate chronic conditions, yet little is known about how individuals with chronic illness use or perceive mobile apps.ObjectiveThe objective of this study was to explore behaviors and perceptions about mobile phone–based apps for health among individuals with chronic conditions.MethodsData were collected from a national cross-sectional survey of 1604 mobile phone users in the United States that assessed mHealth use, beliefs, and preferences. This study examined health app use, reason for download, and perceived efficacy by chronic condition.ResultsAmong participants, having between 1 and 5 apps was reported by 38.9% (314/807) of respondents without a condition and by 6.6% (24/364) of respondents with hypertension. Use of health apps was reported 2 times or more per day by 21.3% (172/807) of respondents without a condition, 2.7% (10/364) with hypertension, 13.1% (26/198) with obesity, 12.3% (20/163) with diabetes, 12.0% (32/267) with depression, and 16.6% (53/319) with high cholesterol. Results of the logistic regression did not indicate a significant difference in health app download between individuals with and without chronic conditions (P>.05). Compared with individuals with poor health, health app download was more likely among those with self-reported very good health (odds ratio [OR] 3.80, 95% CI 2.38-6.09, P<.001) and excellent health (OR 4.77, 95% CI 2.70-8.42, P<.001). Similarly, compared with individuals who report never or rarely engaging in physical activity, health app download was more likely among those who report exercise 1 day per week (OR 2.47, 95% CI 1.6-3.83, P<.001), 2 days per week (OR 4.77, 95% CI 3.27-6.94, P<.001), 3 to 4 days per week (OR 5.00, 95% CI 3.52-7.10, P<.001), and 5 to 7 days per week (OR 4.64, 95% CI 3.11-6.92, P<.001). All logistic regression results controlled for age, sex, and race or ethnicity.ConclusionsResults from this study suggest that individuals with poor self-reported health and low rates of physical activity, arguably those who stand to benefit most from health apps, were least likely to report download and use these health tools.

Highlights d Obesity accelerates oncogenic Kras-driven pancreatic ductal tumorigenesis in mice d Genetic or dietary weight loss intercepts pancreatic cancer progression d Obesity is associated with aberrant pancreatic islet cholecystokinin expression d Islet cholecystokinin overexpression drives pancreatic ductal cancer development

Although it has become increasingly clear that cancers display extensive cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumours remain poorly understood. Here we leverage mosaic analysis with double markers (MADM) to trace subclonal populations retaining or lacking p53 within oncogenic Kras-initiated lung and pancreatic tumours. In both models, p53 constrains progression to advanced adenocarcinomas. Comparison of lineage-related p53 knockout and wild-type clones reveals a minor role of p53 in suppressing cell expansion in lung adenomas. In contrast, p53 loss promotes both the initiation and expansion of low-grade pancreatic intraepithelial neoplasia (PanINs), likely through differential expression of the p53 regulator p19ARF. Strikingly, lineage-related cells are often dispersed in lung adenomas and PanINs, contrasting with more contiguous growth of advanced subclones. Together, these results support cancer type-specific suppressive roles of p53 in early tumour progression and offer insights into clonal growth patterns during tumour development.

This article presents findings from two studies that describe news portrayals of cancer causes and prevention in local TV and test the effects of typical aspects of this coverage on cancer-related fatalism and overload. Study 1 analyzed the content of stories focused on cancer causes and prevention from an October 2002 national sample of local TV and newspaper cancer coverage (n = 122 television stations; n = 60 newspapers). Informed by results from the content analysis, Study 2 describes results from a randomized experiment testing effects of the volume and content of news stories about cancer causes and prevention (n = 601). Study 1 indicates that local TV news stories describe cancer causes and prevention as comparatively more certain than newspapers but include less information about how to reduce cancer risk. Study 2 reveals that the combination of stories conveying an emerging cancer cause and prevention behavior as moderately certain leads to an increased sense of overload, while a short summary of well-established preventive behaviors mitigates these potentially harmful beliefs. We conclude with a series of recommendations for health communication and health journalism practice.

Activating mutations in KRAS are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and the key drivers of its initiation and progression. Longstanding efforts to develop novel KRAS inhibitors have been based on the assumption that PDAC cells are addicted to activated KRAS, but this assumption remains controversial. In this study, we analyzed the requirement of endogenous Kras to maintain survival of murine PDAC cells, using an inducible shRNA-based system that enables temporal control of Kras expression. We found that the majority of murine PDAC cells analyzed tolerated acute and sustained Kras silencing by adapting to a reversible cell state characterized by differences in cell morphology, proliferative kinetics, and tumorinitiating capacity. While we observed no significant mutational or transcriptional changes in the Kras-inhibited state, global phosphoproteomic profiling revealed significant alterations in cell signaling, including increased phosphorylation of focal adhesion pathway components. Accordingly, Kras-inhibited cells displayed prominent focal adhesion plaque structures, enhanced adherence properties, and increased dependency on adhesion for viability in vitro. Overall, our results call into question the degree to which PDAC cells are addicted to activated KRAS, by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade. However, by identifying these mechanisms, our work also provides mechanistic directions to develop combination strategies that can help enforce the efficacy of KRAS inhibitors.Significance: These results call into question the degree to which pancreatic cancers are addicted to KRAS by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade, with implications for the development of KRAS inhibitors for PDAC treatment. Cancer Res; 78(4); 985-1002.Ó2017 AACR.