Grasslands store approximately one third of the global terrestrial carbon stocks and can act as an important soil carbon sink. Recent studies show that plant diversity increases soil organic carbon (SOC) storage by elevating carbon inputs to belowground biomass and promoting microbial necromass contribution to SOC storage. Climate change affects grassland SOC storage by modifying the processes of plant carbon inputs and microbial catabolism and anabolism. Improved grazing management and biodiversity restoration can provide low-cost and/or high-carbon-gain options for natural climate solutions in global grasslands. The achievable SOC sequestration potential in global grasslands is 2.3 to 7.3 billion tons of carbon dioxide equivalents per year (CO₂e year⁻¹) for biodiversity restoration, 148 to 699 megatons of CO₂e year⁻¹ for improved grazing management, and 147 megatons of CO₂e year⁻¹ for sown legumes in pasturelands.

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.

Editor's summary

B cells are white blood cells that produce antibodies and are often found within the tumor microenvironment. Ma et al. examined tumor-infiltrating B cells across 21 different cancer types from more than 270 patients (see the Perspective by Tellier and Nutt). The authors compiled single-cell transcriptome, B cell receptor repertoire, and chromatin accessibility data and report that tumor-associated B cells differentiated into antibody-secreting cells by either an extrafollicular pathway or by a more canonical germinal center pathway. Tumors associated with the extrafollicular B cell profile demonstrated poor clinical prognosis and resistance to immunotherapy compared with tumors harboring germinal center B cells. Alterations in the availability of glutamine-derived metabolites, which are known to influence T cell-dependent immunosuppression, may be linked to a dysfunctional humoral response and the adverse effect of extrafollicular B cells on tumors. —Priscilla N. Kelly

INTRODUCTION

Tumor-infiltrating B cells have emerged as important players in cancer immunity and served as predictors of response to immunotherapy. These B cells display multiple functions, primarily through their ability to differentiate into plasma cells to produce antibodies, but vary spatiotemporally across different cancer types. Dissecting the abundance and differentiation states of B cells across diverse cancer types holds promise for improving the immunotherapeutic response.

RATIONALE

To compile a comprehensive pan-cancer B cell landscape, we performed single-cell RNA sequencing (scRNA-seq) on paired tumors, lymph node metastases, adjacent normal tissues, and peripheral blood from patients with various cancer types, as well as incorporating substantial published scRNA-seq datasets. After correction of the batch effect, this atlas consists of scRNA-seq data from 269 patients across 20 cancer types. We assembled B cell receptor (BCR) sequencing of individual B cells with gene-expression profiles to characterize the dynamic transition between B cells and antibody-secreting cells (ASCs). We integrated the single-cell chromatin accessibility landscape of B cells from different cancers to dissect the epigenomic regulation networks that function in fine-tuning B cell development. We spatially localized B cells in mature versus immature tertiary lymphoid structures (TLSs) and investigated the potential regulators that direct B cells into specific responses.

RESULTS

We revealed substantial heterogeneity within B and plasma cells, identifying 15 B cell subsets and 10 plasma cell subsets. We computationally derived and validated two independent developmental pathways to ASCs through canonical germinal center (GC) and alternative extrafollicular (EF) pathways and demonstrated an apparent cancer-type preference. Colon adenocarcinoma and liver hepatocellular carcinoma were the two representative types of cancer enriched for GC and EF pathways, respectively. We affirmed that EF-dominant cancers correlate with dysregulated immune responses and worse clinical outcomes. We then identified the dynamic metabolic-epigenetic-signaling networks engaged in fine-tuning tumor-infiltrating B cell differentiation and managing the balance between the EF and GC pathways. Atypical memory (AtM) B cells, the primary progenitors of EF-derived ASCs, exhibit an exhausted and bystander phenotype and develop independently of the GC pathway. We found that the AtM B cells reside in the center of immature TLSs and spatially relocate to the periphery during TLS maturation. Last, we mechanistically linked these findings to specific transcription factors and epigenomic regulations. We demonstrated that the glutamine-derived metabolite α-ketoglutarate (α-KG) could increase the expression of AtM B cell-associated transcription factors T-bet and BATF and promote their differentiation, accompanied by the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Consequently, AtM B cells acquire an immunoregulatory function that dampens antitumor T cell responses and fosters an immunosuppressive microenvironment.

CONCLUSION

We compiled the blueprint of B cell heterogeneity and two dynamic differentiation pathways in human cancers, providing a fundamental reference of ASC differentiation trajectory for future studies. The systematic comparison between EF and GC pathways reveals the similarities and differences of B cell states across different cancer types, highlighting the unfavorable clinical outcome linked to the immunosuppressive microenvironment of EF pathway-associated AtM B cells. Metabolic-epigenetic networks are remarkably flexible and can reconfigure B cell fates in a way that will facilitate the development of B cell-targeted immunotherapies.