Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.
Objective A history of periodontal disease and the presence of circulating antibodies to selected oral pathogens have been associated with increased risk of pancreatic cancer; however, direct relationships of oral microbes with pancreatic cancer have not been evaluated in prospective studies. We examine the relationship of oral microbiota with subsequent risk of pancreatic cancer in a large nested case-control study. Design We selected 361 incident adenocarcinoma of pancreas and 371 matched controls from two prospective cohort studies, the American Cancer Society Cancer Prevention Study II and the National Cancer Institute Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. From pre-diagnostic oral wash samples, we characterised the composition of the oral microbiota using bacterial 16S ribosomal RNA (16S rRNA) gene sequencing. The associations between oral microbiota and risk of pancreatic cancer, controlling for the random effect of cohorts and other covariates, were examined using traditional and L1-penalised least absolute shrinkage and selection operator logistic regression. Results Carriage of oral pathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, were associated with higher risk of pancreatic cancer (adjusted OR for presence vs absence=1.60 and 95% CI 1.15 to 2.22; OR=2.20 and 95% CI 1.16 to 4.18, respectively). Phylum Fusobacteria and its genus Leptotrichia were associated with decreased pancreatic cancer risk (OR per per cent increase of relative abundance=0.94 and 95% CI 0.89 to 0.99; OR=0.87 and 95% CI 0.79 to 0.95, respectively). Risks related to these phylotypes remained after exclusion of cases that developed within 2 years of sample collection, reducing the likelihood of reverse causation in this prospective study. Conclusions This study provides supportive evidence that oral microbiota may play a role in the aetiology of pancreatic cancer.
This study demonstrates that greater oral abundance of commensal Corynebacterium and Kingella is associated with decreased risk of HNSCC, with potential implications for cancer prevention.
CTLA-4 blockade leads to enhanced activation of tumor-reactive T cells with concomitant up-regulation of ICOS, thus enabling their responses to be enhanced by ICOS engagement.
BackgroundDysbiosis of the oral microbiome can lead to local oral disease and potentially to cancers of the head, neck, and digestive tract. However, little is known regarding exogenous factors contributing to such microbial imbalance.ResultsWe examined the impact of alcohol consumption on the oral microbiome in a cross-sectional study of 1044 US adults. Bacterial 16S rRNA genes from oral wash samples were amplified, sequenced, and assigned to bacterial taxa. We tested the association of alcohol drinking level (non-drinker, moderate drinker, or heavy drinker) and type (liquor, beer, or wine) with overall microbial composition and individual taxon abundance. The diversity of oral microbiota and overall bacterial profiles differed between heavy drinkers and non-drinkers (α-diversity richness p = 0.0059 and β-diversity unweighted UniFrac p = 0.0036), and abundance of commensal order Lactobacillales tends to be decreased with higher alcohol consumption (fold changes = 0.89 and 0.94 for heavy and moderate drinkers, p trend = 0.005 [q = 0.064]). Additionally, certain genera were enriched in subjects with higher alcohol consumption, including Actinomyces, Leptotrichia, Cardiobacterium, and Neisseria; some of these genera contain oral pathogens, while Neisseria can synthesize the human carcinogen acetaldehyde from ethanol. Wine drinkers may differ from non-drinkers in microbial diversity and profiles (α-diversity richness p = 0.048 and β-diversity unweighted UniFrac p = 0.059) after controlling for drinking amount, while liquor and beer drinkers did not. All significant differences between drinkers and non-drinkers remained after exclusion of current smokers.ConclusionsOur results, from a large human study of alcohol consumption and the oral microbiome, indicate that alcohol consumption, and heavy drinking in particular, may influence the oral microbiome composition. These findings may have implications for better understanding the potential role that oral bacteria play in alcohol-related diseases.Electronic supplementary materialThe online version of this article (10.1186/s40168-018-0448-x) contains supplementary material, which is available to authorized users.
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