Netie: inferring the evolution of neoantigen-T cell interactions in tumors.

Neoantigens are the key targets of antitumor immune responses from cytotoxic T cells and play a critical role in affecting tumor progressions and immunotherapy treatment responses. However, little is known about how the interaction between neoantigens and T cells ultimately affects the evolution of cancerous masses. Here, we develop a hierarchical Bayesian model, named neoantigen-T cell interaction estimation (netie) to infer the history of neoantigen-CD8+ T cell interactions in tumors. Netie was systematically validated and applied to examine the molecular patterns of 3,219 tumors, compiled from a panel of 18 cancer types. We showed that tumors with an increase in immune selection pressure over time are associated with T cells that have an activation-related expression signature. We also identified a subset of exhausted cytotoxic T cells postimmunotherapy associated with tumor clones that newly arise after treatment. These analyses demonstrate how netie enables the interrogation of the relationship between individual neoantigen repertoires and the tumor molecular profiles. We found that a T cell inflammation gene expression profile (TIGEP) is more predictive of patient outcomes in the tumors with an increase in immune pressure over time, which reveals a curious synergy between T cells and neoantigen distributions. Overall, we provide a new tool that is capable of revealing the imprints left by neoantigens during each tumor's developmental process and of predicting how tumors will progress under further pressure of the host's immune system.

The histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics.

Histology plays an essential role in therapeutic decision-making for lung cancer patients. However, the molecular determinants of lung cancer histology are largely unknown. We conduct whole-exome sequencing and microarray profiling on 19 micro-dissected tumor regions of different histologic subtypes from 9 patients with lung cancers of mixed histology. A median of 68.9% of point mutations and 83% of copy number aberrations are shared between different histologic components within the same tumors. Furthermore, different histologic components within the tumors demonstrate similar subclonal architecture. On the other hand, transcriptomic profiling reveals shared pathways between the same histologic subtypes from different patients, which is supported by the analyses of the transcriptomic data from 141 cell lines and 343 lung cancers of different histologic subtypes. These data derived from mixed histologic subtypes in the setting of identical genetic background and exposure history support that the histologic fate of lung cancer cells is associated with transcriptomic features rather than the genomic profiles in most tumors.

Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer.

BACKGROUND: Osimertinib is the treatment of choice for advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, novel strategies to improve the duration of disease control are still urgently needed. Aspirin has been shown to decrease cancer incidence and improve outcomes in various malignancies. Therefore, we evaluated a cohort of patients who received osimertinib with or without concurrent use of aspirin to assess whether the addition of aspirin may lead to improved clinical outcomes. METHODS: MD Anderson Cancer Center GEMINI database was retrospectively queried for EGFR-mutant NSCLC patients who received osimertinib with or without concurrent use of aspirin for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 365 patients were identified including 77 which had concurrent use of aspirin. Patients in the aspirin-osimertinib group had significantly improved PFS (21.3 vs 11.6 months; HR, 0.52; 95 % CI, 0.38-0.70) and OS (Not reached vs 32.3 months; HR, 0.56; 95 % CI, 0.35-0.91) compared to osimertinib group. In subgroup analyses, the aspirin-associated PFS benefit was observed in patients with and without central nervous system (CNS) metastases, as well as in osimertinib first-line setting and in subsequent line setting. The median PFS in EGFR 19Del patients was longer than EGFR L858R patients with osimertinib, and when aspirin was added, the median PFS significantly improved in both groups regardless of lines of therapy. The benefit from aspirin was independent of age, gender, TP53 mutational status, or PD-L1 positivity. CONCLUSION: Concurrent aspirin use with osimertinib in EGFR-mutant NSCLC patients was associated with improved survival, regardless of lines of therapy, CNS metastatic status, EGFR mutation type, age, gender, TP53, and PD-L1 status.

The Role of Housing Environment and Dietary Protein Source on the Gut Microbiota of Chicken.

The gut microbiota of chicken has received much attention due to its importance for bird health, food safety, and performance. In the United States, the impending transition to cage-free housing environments has raised many questions about its consequences for poultry health, productivity, and welfare. Therefore, we investigated how housing environments and feed composition affect the poultry gut microbiome. Such data is necessary to inform the design of production systems that promote health and food safety. In this study, we investigated the cecal microbiome of both caged and cage-free laying hens that were fed either an industry-standard soy-based versus a soy-free diet. Caged hens were housed in standard industry-style layer cages with one bird per cage, and cage-free hens were housed in a poultry barn with an outdoor enclosed yard with multiple hens per pen. Our study showed significant differences in the gut microbiota between cage-free and caged environments. Cage free housing generated higher diversity compared to caged housing. Furthermore, we observed a synergistic interaction of soy-based feed in cage-free housing, as the cage-free soy group showed the highest alpha diversity, whereas the caged-soy group showed the lowest diversity overall.

Circadian disruption and divergent microbiota acquisition under extended photoperiod regimens in chicken.

The gut microbiota is crucial for metabolic homeostasis, immunity, growth and overall health, and it is recognized that early-life microbiota acquisition is a pivotal event for later-life health. Recent studies show that gut microbiota diversity and functional activity are synchronized with the host circadian rhythms in healthy individuals, and circadian disruption elicits dysbiosis in mammalian models. However, no studies have determined the associations between circadian disruption in early life, microbiota colonization, and the consequences for microbiota structure in birds. Chickens, as a major source of protein around the world, are one of the most important agricultural species, and their gut and metabolic health are significant concerns. The poultry industry routinely employs extended photoperiods (>18 h light) as a management tool, and their impacts on the chicken circadian, its role in gut microbiota acquisition in early life (first 3 weeks of life), and consequences for later life microbiota structure remain unknown. In this study, the objectives were to (a) characterize circadian activity under two different light regimes in layer chicken (12/12 h' Light/Dark (LD) and 23/1 h LD), (b) characterize gut microbiota acquisition and composition in the first 4 weeks of life, (c) determine if gut microbiota oscillate in synchrony with the host circadian rhythm, and (d) to determine if fecal microbiota is representative of cecal microbiota in early life. Expression of clock genes (clock, bmal1, and per2) was assayed, and fecal and cecal microbiotas were characterized using 16S rRNA gene amplicon analyses from birds raised under two photoperiod treatments. Chickens raised under 12/12 LD photoperiods exhibited rhythmic clock gene activity, which was absent in birds raised under the extended (23/1 LD) photoperiod. There was differential microbiota acquisition under different photoperiod regimes in newly hatched chicks. Gut microbiota members showed a similar oscillating pattern as the host, but this association was not as strong as found in mammals. Finally, the fecal microbiota was found to be not representative of cecal microbiota membership and structure in young birds. This is one of the first studies to demonstrate the use of photoperiods to modulate microbiota acquisition in newly hatched chicks, and show their potential as a tool to promote the colonization of beneficial microorganisms.