Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.
The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy 1,2 . However, measuring tumour infiltrating lymphocytes (TILs) is restricted by lack of appropriate data. Whole exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations.Here we develop a method for T cell fraction estimation from WES samples, utilising a signal from T cell receptor excision circle (TRECs) loss during VDJ recombination of the T cell receptor alpha (TCRA) gene. This score significantly correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma and using a meta-analysis of immunotherapy-treated tumours, we show that this score predicts immunotherapy response, providing value beyond tumour mutational burden. Applying this score to a multi-sample pancancer cohort revealed high diversity in immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, was associated with reduced TCRA T cell fraction. Our method, T cell ExTRECT (T cell Exome TREC Tool), quantifies the T cell infiltrate of WES samples.Here we propose a method for the estimation of the T cell fraction present in a WES sample. This method utilises a somatic copy number-based signal from VDJ recombination and the loss of TRECs. We explore the underlying features which predict T cell infiltrate in tumours and blood and evaluate determinants of immune heterogeneity within tumours. Finally, we demonstrate that our estimated T cell fraction can be used as a predictor of clinical response to CPI therapy. Results Inferring T cell fraction from WES dataT cell diversity, which is required for immune system recognition of foreign antigens, is a product of VDJ recombination, where segments within the T cell receptor genes recombine.The alpha chain of the T cell receptor is encoded by the TCRA gene (also known as TRA) and the result of VDJ recombination is the excision of unselected gene segments from TCRA as TRECs, with the T cell undergoing a deletion event within TCRA.Tools to infer cancer somatic copy number alteration (SCNA) [6][7][8][9] rely on the read depth ratio (RDR), reflecting the log of the ratio of reads between the tumour sample and its matched control (e.g. buffy coat in a centrifuged blood sample). Deviation in the RDR from zero is assumed to reflect a tumour SCNA. However, within TCRA this assumption does not hold; a deviance in the RDR may reflect T cell specific deletion events and SCNA tools may thus erroneously infer tumour SCNA. Indeed, in the TRACERx100 cohort multiple SCNA within TCRA were inferred in 165/327 tumour regions (Extended Data Fig. 1a). The RDR deviated the most within segments frequently included within TRECs (Extended Data Fig. 1b-c). This suggests that most detected SCNAs within TCRA...
Ribonucleic acids (RNAs) mainly played auxiliary roles in regulations of genetic processes while recent explorations into small non-coding RNAs (sRNAs) in bacteria have broadened the scope of RNAs studies in these processes. sRNAs have been demonstrated to be involved in various genetic processes and to regulate a variety of bacterial physiologies. Comparatively, quorum sensing (QS) is a mature bacterial cell signaling system which regulates bacteria physiologies as well. Prokaryotic sRNAs studies in the status quo have revealed an emerging picture of trans-kingdom signaling regulation and increasing investigations have demonstrated the feasibility of inter-kingdom signaling as the consequence of QS. We therefore review such phenomena and their similarities to investigate the potential of prokaryote-sourced interkingdom signaling and regulation.
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