Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials.

BACKGROUND: The immune status of a patient's tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients' immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms. METHODS: We systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I-III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+tumor-infiltrating lymphocytes in the TME. RESULTS: The CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve inflamed=0.846; excluded=0.712; desert=0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (HR 0.88; 95% CI 0.80 to 0.97) across TCGA, and longer OS on immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI 0.58 to 0.97). CONCLUSIONS: We provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy.

Large-scale whole-genome resequencing unravels the domestication history of Cannabis sativa.

Cannabis sativa has long been an important source of fiber extracted from hemp and both medicinal and recreational drugs based on cannabinoid compounds. Here, we investigated its poorly known domestication history using whole-genome resequencing of 110 accessions from worldwide origins. We show that C. sativa was first domesticated in early Neolithic times in East Asia and that all current hemp and drug cultivars diverged from an ancestral gene pool currently represented by feral plants and landraces in China. We identified candidate genes associated with traits differentiating hemp and drug cultivars, including branching pattern and cellulose/lignin biosynthesis. We also found evidence for loss of function of genes involved in the synthesis of the two major biochemically competing cannabinoids during selection for increased fiber production or psychoactive properties. Our results provide a unique global view of the domestication of C. sativa and offer valuable genomic resources for ongoing functional and molecular breeding research.

Correction to: Rapid turnover of life-cycle-related genes in the brown algae.

Following publication of the original article [1], it was noticed that the author names were published with initials instead of full names. The article [1] has been updated.

Rapid turnover of life-cycle-related genes in the brown algae.

BACKGROUND: Sexual life cycles in eukaryotes involve a cyclic alternation between haploid and diploid phases. While most animals possess a diploid life cycle, many plants and algae alternate between multicellular haploid (gametophyte) and diploid (sporophyte) generations. In many algae, gametophytes and sporophytes are independent and free-living and may present dramatic phenotypic differences. The same shared genome can therefore be subject to different, even conflicting, selection pressures during each of the life cycle generations. Here, we analyze the nature and extent of genome-wide, generation-biased gene expression in four species of brown algae with contrasting levels of dimorphism between life cycle generations. RESULTS: We show that the proportion of the transcriptome that is generation-specific is broadly associated with the level of phenotypic dimorphism between the life cycle stages. Importantly, our data reveals a remarkably high turnover rate for life-cycle-related gene sets across the brown algae and highlights the importance not only of co-option of regulatory programs from one generation to the other but also of a role for newly emerged, lineage-specific gene expression patterns in the evolution of the gametophyte and sporophyte developmental programs in this major eukaryotic group. Moreover, we show that generation-biased genes display distinct evolutionary modes, with gametophyte-biased genes evolving rapidly at the coding sequence level whereas sporophyte-biased genes tend to exhibit changes in their patterns of expression. CONCLUSION: Our analysis uncovers the characteristics, expression patterns, and evolution of generation-biased genes and underlines the selective forces that shape this previously underappreciated source of phenotypic diversity.

Early Arrival and Climatically-Linked Geographic Expansion of New World Monkeys from Tiny African Ancestors.

New World Monkeys (NWM) (platyrrhines) are one of the most diverse groups of primates, occupying today a wide range of ecosystems in the American tropics and exhibiting large variations in ecology, morphology, and behavior. Although the relationships among the almost 200 living species are relatively well understood, we lack robust estimates of the timing of origin, ancestral morphology, and geographic range evolution of the clade. Herein, we integrate paleontological and molecular evidence to assess the evolutionary dynamics of extinct and extant platyrrhines. We develop novel analytical frameworks to infer the evolution of body mass, changes in latitudinal ranges through time, and species diversification rates using a phylogenetic tree of living and fossil taxa. Our results show that platyrrhines originated 5-10 million years earlier than previously assumed, dating back to the Middle Eocene. The estimated ancestral platyrrhine was small-weighing 0.4 kg-and matched the size of their presumed African ancestors. As the three platyrrhine families diverged, we recover a rapid change in body mass range. During the Miocene Climatic Optimum, fossil diversity peaked and platyrrhines reached their widest latitudinal range, expanding as far South as Patagonia, favored by warm and humid climate and the lower elevation of the Andes. Finally, global cooling and aridification after the middle Miocene triggered a geographic contraction of NWM and increased their extinction rates. These results unveil the full evolutionary trajectory of an iconic and ecologically important radiation of monkeys and showcase the necessity of integrating fossil and molecular data for reliably estimating evolutionary rates and trends.

Transcriptomic resources for an endemic Neotropical plant lineage (Gesneriaceae).

PREMISE OF THE STUDY: Despite the extensive phenotypic variation that characterizes the Gesneriaceae family, there is a lack of genomic resources to investigate the molecular basis of their diversity. We developed and compared the transcriptomes for two species of the Neotropical lineage of the Gesneriaceae. METHODS AND RESULTS: Illumina sequencing and de novo assembly of floral and leaf samples were used to generate multigene sequence data for Sinningia eumorpha and S. magnifica, two species endemic to the Brazilian Atlantic Forest. A total of 300 million reads were used to assemble the transcriptomes, with an average of 92,038 transcripts and 43,506 genes per species. The transcriptomes showed good quality metrics, with the presence of all eukaryotic core genes, and an equal representation of clusters of orthologous groups (COG) classifications between species. The orthologous search produced 8602 groups, with 15-20% of them annotated using BLAST tools. DISCUSSION: This study provides the first step toward a comprehensive multispecies transcriptome characterization of the Gesneriaceae family. These resources are the basis for comparative analyses in this species-rich Neotropical plant group; they will also allow the investigation of the evolutionary importance of multiple metabolic pathways and phenotypic diversity, as well as developmental programs in these nonmodel species.

Gene pools in wild Lima bean (Phaseolus lunatus L.) from the Americas: evidences for an Andean origin and past migrations.

The aims of this research were to assess the genetic structure of wild Phaseolus lunatus L. in the Americas and the hypothesis of a relatively recent Andean origin of the species. For this purpose, nuclear and non-coding chloroplast DNA markers were analyzed in a collection of 59 wild Lima bean accessions and six allied species. Twenty-three chloroplast and 28 nuclear DNA haplotypes were identified and shown to be geographically structured. Three highly divergent wild Lima bean gene pools, AI, MI, and MII, with mostly non-overlapping geographic ranges, are proposed. The results support an Andean origin of wild Lima beans during Pleistocene times and an early divergence of the three gene pools at an age that is posterior to completion of the Isthmus of Panama and major Andean orogeny. Gene pools would have evolved and reached their current geographic distribution mainly in isolation and therefore are of high priority for conservation and breeding programs.