Alterations of gut microbiota have been implicated in multiple diseases including cancer. However, the gut microbiota spectrum in lung cancer remains largely unknown. Here we profiled the gut microbiota composition in a discovery cohort containing 42 early-stage lung cancer patients and 65 healthy individuals through the 16S ribosomal RNA (rRNA) gene sequencing analysis. We found that lung cancer patients displayed a significant shift of microbiota composition in contrast to the healthy populations. To identify the optimal microbiota signature for noninvasive diagnosis purpose, we took advantage of Support-Vector Machine (SVM) and found that the predictive model with 13 operational taxonomic unit (OTU)-based biomarkers achieved a high accuracy in lung cancer prediction (area under curve, AUC = 97.6%). This signature performed reasonably well in the validation cohort (AUC = 76.4%), which contained 34 lung cancer patients and 40 healthy individuals. To facilitate potential clinical practice, we further constructed a 'patient discrimination index' (PDI), which largely retained the prediction efficiency in both the discovery cohort (AUC = 92.4%) and the validation cohort (AUC = 67.7%). Together, our study uncovered the microbiota spectrum of lung cancer patients and established the specific gut microbial signature for the potential prediction of the early-stage lung cancer.
Highlights d Fever promotes a4-integrin-mediated T cell adhesion and transmigration d Hsp90 binds to a4 tails and activates a4 integrins via insideout signaling d Hsp90 triggers dimerization and clustering of a4 integrins to activate FAK-RhoA d Disruption of Hsp90-a4 interaction impairs fever-induced T cell trafficking SUMMARYFever is an evolutionarily conserved response that confers survival benefits during infection. However, the underlying mechanism remains obscure. Here, we report that fever promoted T lymphocyte trafficking through heat shock protein 90 (Hsp90)induced a4 integrin activation and signaling in T cells. By inducing selective binding of Hsp90 to a4 integrins, but not b2 integrins, fever increased a4-integrin-mediated T cell adhesion and transmigration. Mechanistically, Hsp90 bound to the a4 tail and activated a4 integrins via inside-out signaling. Moreover, the N and C termini of one Hsp90 molecule simultaneously bound to two a4 tails, leading to dimerization and clustering of a4 integrins on the cell membrane and subsequent activation of the FAK-RhoA pathway. Abolishment of Hsp90-a4 interaction inhibited fever-induced T cell trafficking to draining lymph nodes and impaired the clearance of bacterial infection. Our findings identify the Hsp90-a4-integrin axis as a thermal sensory pathway that promotes T lymphocyte trafficking and enhances immune surveillance during infection.
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