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Key Points The traditional view is that innate immunity has a long phylogenetic history, whereas conventional adaptive immunity is restricted to jawed vertebrates. However, recent studies have shown that there might be alternative forms of adaptive immunity in jawless vertebrates and invertebrates and that diversified immune receptors are far more broadly distributed in phylogeny than was previously thought. Mediators of adaptive and innate immunity use related mechanisms to diversify structural domains in immune receptors. Pathogens use similar methods of genetic change to diversify many of the same types of domain to evade host immune defences. Various mechanisms are used to generate diversity in immune effector molecules. Depending on the level of phylogenetic development, different mechanisms or combinations of these mechanisms might be used to carry out these processes. Lymphocyte-like cells are seen in jawless vertebrates despite the apparent absence of authentic B- and T-cell-receptor homologues in these species. A leucine-rich-repeat-encoding gene that undergoes rearrangement in single lymphocytes is a possible mediator of adaptive immunity in both extant groups of jawless vertebrates (lampreys and hagfish). Natural killer (NK)-cell immunity seems to have a long phylogenetic history. Members of a family of authentic variable-region-containing activating and inhibitory type I transmembrane proteins that is found in bony fish share several properties with killer-cell immunoglobulin-like receptors (KIRs), which are the main family of diversified NK-cell receptors in humans. The enormously complex conventional adaptive immune system, which uses segmental rearrangement of variable, diversity and joining elements, has been assembled during evolution by integrating molecules that are involved in unrelated aspects of cellular metabolism. Furthermore, many of these same molecules are used to effect other germline changes during the developmental maturation of single lymphocytes. Both the innate and adaptive immune systems use an unexpectedly large number of different solutions in terms of receptor variation to solve the similar problem of host defence against infectious challenge. Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1 – 7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act. Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

In this study, we compared immunoglobulin heavy-chain-gene-based minimal residual disease (MRD) detection by real-time quantitative PCR (RQ-PCR) and next-generation sequencing (NGS) to assess whether NGS could overcome some limitations of RQ-PCR and further increase sensitivity, specificity, accuracy and reproducibility. In total, 378 samples from 55 patients with acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) or multiple myeloma (MM) were investigated for clonotype identification, clonotype identity and comparability of MRD results. Forty-five clonotypes were identified by RQ-PCR and 49 by NGS. Clonotypes identified by both tools were identical or >97% homologous in 96% of cases. Both tools were able to routinely reach a sensitivity level of 1 × E−05. A good correlation of MRD results was observed ( R =0.791, P <0.001), with excellent concordance in 79.6% of cases. Few discordant cases were observed across all disease subtypes. NGS showed at least the same level of sensitivity as allele-specific oligonucleotides-PCR, without the need for patient-specific reagents. We conclude that NGS is an effective tool for MRD monitoring in ALL, MCL and MM. Prospective comparative analysis of unselected cases is required to validate the clinical impact of NGS-based MRD assessment.

Glucocorticoids (GCs) are small lipid hormones produced by the adrenals that maintain organismal homeostasis. Circadian and stress-induced changes in systemic GC levels regulate metabolism, cardiovascular and neural function, reproduction and immune activity. Our understanding of GC effects on immunity comes largely from administration of exogenous GCs to treat immune or inflammatory disorders. However, it is increasingly clear that endogenous GCs both promote and suppress T cell immunity. Examples include selecting an appropriate repertoire of T cell receptor (TCR) self-affinities in the thymus, regulating T cell trafficking between anatomical compartments, suppressing type 1 T helper (TH1) cell responses while permitting TH2 cell and, especially, IL-17-producing T helper cell responses, and promoting memory T cell differentiation and maintenance. Furthermore, in addition to functioning at a distance, extra-adrenal (local) production allows GCs to act as paracrine signals, specifically targeting activated T cells in various contexts in the thymus, mucosa and tumours. These pleiotropic effects on different T cell populations during development and immune responses provide a nuanced understanding of how GCs shape immunity.Glucocorticoid treatment is used to suppress the immune system in various disease settings. However, endogenous glucocorticoids are able to promote as well as inhibit different aspects of T cell immunity. Here, the authors discuss the many ways in which T cell responses are shaped by glucocorticoids.

The traditional approach to the treatment of patients with advanced-stage non-small-cell lung carcinoma (NSCLC) harbouring ALK rearrangements or EGFR mutations has been the sequential administration of therapies (sequential treatment approach), in which patients first receive first-generation tyrosine-kinase inhibitors (TKIs), which are eventually replaced by next-generation TKIs and/or chemotherapy upon disease progression, in a decision optionally guided by tumour molecular profiling. In the past few years, this strategy has been challenged by clinical evidence showing improved progression-free survival, improved intracranial disease control and a generally favourable toxicity profile when next-generation EGFR and ALK TKIs are used in the first-line setting. In this Review, we describe the existing preclinical and clinical evidence supporting both treatment strategies — the ‘historical’ sequential treatment strategy and the use of next-generation TKIs — as frontline therapies and discuss the suitability of both strategies for patients with EGFR-driven or ALK-driven NSCLC.

Evidence has demonstrated that monitoring of the variable, diversity, and joining gene segments (VDJ) rearrangement of immunoglobulin (Ig) gene in the circulating tumor DNA (ctDNA) is highly valuable in predicting the prognosis of patients with diffuse large B cell lymphoma (DLBCL). In this study, we investigated the role of both Ig heavy chain (IGH) and Ig kappa light chain (IGK) gene rearrangements detected in ctDNA samples in predicting DLBCL progression. Next-generation sequencing (NGS) was used to identify the dominant V(D)J clonotypic rearrangement in tissue samples of 33 DLBCL patients. Minimal residual disease (MRD) was monitored at the interim and end of the treatment, as well as the follow-up time by tracking the dominant V(D)J clonotypic rearrangement (defined as the \"NGS MRD\" method) in the peripheral blood (PB) ctDNA samples. The nomogram was established to predict the 12-month and 24-month progression-free survival (PFS) probability. Prior to treatment, the dominant clones identified in the tissue samples could be retrieved in tissue-matched PB of 26 (78.8%, 26/33) patients. The addition of IGK clones to IGH clones increased the MRD detection rate from 42.9% to 58.0% in the total series. NGS MRD and imaging scans showed poor concordance at the interim of treatment (Kappa = 0.24) and the follow-up time (Kappa = 0.28), and fair concordance at the end of treatment (Kappa = 0.46). However, we confirmed that the interim NGS MRD monitoring demonstrated improved prognostic performance compared to imaging scans, and both NGS MRD monitoring and imaging scans served as valuable prognostic factors for PFS at the end of treatment. Notably, NGS MRD monitoring predicted disease relapse in 3 patients prior to imaging scans. Furthermore, we found that both the faster IGH and IGK clone clearance rates were associated with favorable prognosis. The nomogram model identified IGH and IGK clone clearance rates, together with the interim NGS MRD result were the important predictors of 12-month and 24-month progression of DLBCL. MRD monitoring via NGS of Ig for both IGH and IGK is a promising noninvasive tool for prognosis prediction and early relapse prediction of DLBCL patients.

Assessment of clonality, marker identification and measurement of minimal residual disease (MRD) of immunoglobulin (IG) and T cell receptor (TR) gene rearrangements in lymphoid neoplasms using next-generation sequencing (NGS) is currently under intensive development for use in clinical diagnostics. So far, however, there is a lack of suitable quality control (QC) options with regard to standardisation and quality metrics to ensure robust clinical application of such approaches. The EuroClonality-NGS Working Group has therefore established two types of QCs to accompany the NGS-based IG/TR assays. First, a central polytarget QC (cPT-QC) is used to monitor the primer performance of each of the EuroClonality multiplex NGS assays; second, a standardised human cell line-based DNA control is spiked into each patient DNA sample to work as a central in-tube QC and calibrator for MRD quantification (cIT-QC). Having integrated those two reference standards in the ARResT/Interrogate bioinformatic platform, EuroClonality-NGS provides a complete protocol for standardised IG/TR gene rearrangement analysis by NGS with high reproducibility, accuracy and precision for valid marker identification and quantification in diagnostics of lymphoid malignancies.

Mammalian T cell receptor (TCR) beta-chain (TRB) V-D-J rearrangement mainly follows the “12/23 rule”, and the “D-J rearrangement preceding the V-(D-J) rearrangement”. Owing to the physical position of the D-J-C cluster in the TRB locus, the TRBD2 (D2) gene cannot directly perform inversional rearrangement or deletional/loop-out rearrangement with the TRBJ1 (J1) gene. Our previous studies revealed a single reverse TRBV30 (TRBV31 in mice) gene in the mammalian TRB locus, which can cause indirect rearrangement of the D2 gene and J1 gene; however, the mechanism and proportion involved in germline gene rearrangement are unknown. We obtained TRB CDR3 repertoires of thymus and peripheral tissues from humans and mice by HTS and scTCR-seq and found that 14% of the rearrangements in which the D2 gene is involved are D2-J1 rearrangements (D2-J2 rearrangements account for approximately 86%). The mechanism is that the reverse V30 gene preferentially performs inversional rearrangement with the D2 gene (V30-D2), leading to V30-D2-J1 rearrangement in humans, or the reverse V30 gene preferentially performs inversional rearrangement with the D1 gene (V30-D1), allowing the forward V genes (Vx) to perform Vx-D2-J1 rearrangement. We further found that D2-J1 rearrangements were present in more than 24% and more than 15% of the D2 gene rearrangements in rhesus monkeys and bats, respectively. Moreover, in bovine containing D1J1C1, D3J3C3, and D2J2C2 clusters, more than 11% D3-J1 and D2-J1 rearrangements and more than 22% D2-J3 rearrangements were found. This study provides a new perspective and feasible solution for further research on the significance of the special V-D-J recombination pattern in the mammalian TRB locus and the CDR3 repertoire formed by D2-J1 rearrangement.

Vertebrate mitochondrial genomes have been extensively studied for genetic and evolutionary purposes, these are normally believed to be extremely conserved, however, different cases of gene rearrangements have been reported. To verify the level of rearrangement and the mitogenome evolution, we performed a comparative genomic analysis of the 2831 vertebrate mitochondrial genomes representing 12 classes available in the NCBI database. Using a combination of bioinformatics methods, we determined there is a high number of errors in the annotation of mitochondrial genes, especially in tRNAs. We determined there is a large variation in the proportion of rearrangements per gene and per taxonomic class, with higher values observed in Actinopteri, Amphibia and Reptilia. We highlight that these are results for currently available vertebrate sequences, so an increase in sequence representativeness in some groups may alter the rearrangement rates, so in a few years it would be interesting to see if these rates are maintained or altered with the new mitogenome sequences. In addition, within each vertebrate class, different patterns in rearrangement proportion with distinct hotspots in the mitochondrial genome were found. We also determined that there are eleven convergence events in gene rearrangement, nine of which are new reports to the scientific community.

Due to groundbreaking developments and continuous progress, the treatment of advanced and metastatic non-small cell lung cancer (NSCLC) has become an exciting, but increasingly challenging task. This applies, in particular, to the subgroup of NSCLC with oncogenic driver alterations. While the treatment of epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC with various tyrosine kinase inhibitors (TKIs) is well-established, new targets have been identified in the last few years and new TKIs introduced in clinical practice. Even for KRAS mutations, considered for a long time as an “un-targetable” alteration, promising new drugs are emerging. The detection and in-depth molecular analysis of resistance mechanisms has further fueled the development of new therapeutic strategies. The objective of this review is to give a comprehensive overview on the current landscape of targetable oncogenic alterations in NSCLC.