No abstract

Highlights d Endogenous retrovirus sensing is required for commensalspecific immunity d Reverse transcription inhibition impairs commensal-induced immunity in the skin d cGAS/STING signaling in keratinocytes is required for skin immunity to the microbiota d Enhanced endogenous retrovirus expression promotes microbiota-induced inflammation

BackgroundMyelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear, induction of endogenous retroelements (EREs) has been hypothesised.MethodsUsing RNA sequencing (RNA-seq), we compared the transcription of EREs in bone marrow HSCs from a new cohort of MDS and chronic myelomonocytic leukaemia (CMML) patients before and after 5-AZA treatment with HSCs from healthy donors and AML patients. We further examined ERE transcription using the most comprehensive annotation of ERE-overlapping transcripts expressed in HSCs, generated here by de novo transcript assembly and supported by full-length RNA-seq.ResultsConsistent with prior reports, we found that treatment with 5-AZA increased the representation of ERE-derived RNA-seq reads in the transcriptome. However, such increases were comparable between treatment responses and failures. The extended view of HSC transcriptional diversity offered by de novo transcript assembly argued against 5-AZA-responsive EREs as determinants of the outcome of therapy. Instead, it uncovered pre-treatment expression and alternative splicing of developmentally regulated gene transcripts as predictors of the response of MDS and CMML patients to 5-AZA treatment.ConclusionsOur study identifies the developmentally regulated transcriptional signatures of protein-coding and non-coding genes, rather than EREs, as correlates of a favourable response of MDS and CMML patients to 5-AZA treatment and offers novel candidates for further evaluation.

Highlights d 115 pre-and post-nivolumab multiregion tumor samples in a prospective phase II study d Maintenance of pre-treatment expanded TCR clones associates with response d Expanded CD8 + T cells upregulate GZMB/K in responders d HERV expression reflects tumor purity and indirectly correlates with response