ABSTRACT
Characterizing the compositional and phenotypic characteristics of tumor-infiltrating B cells (TIBs) is important for advancing our understanding of their role in cancer development. Here, we establish a comprehensive resource of human B cells by integrating single-cell RNA sequencing data of B cells from 649 patients across 19 major cancer types. We demonstrate substantial heterogeneity in their total abundance and subtype composition and observe immunoglobulin G (IgG)-skewness of antibody-secreting cell isotypes. Moreover, we identify stress-response memory B cells and tumor-associated atypical B cells (TAABs), two tumor-enriched subpopulations with prognostic potential, shared in a pan-cancer manner. In particular, TAABs, characterized by a high clonal expansion level and proliferative capacity as well as by close interactions with activated CD4 T cells in tumors, are predictive of immunotherapy response. Our integrative resource depicts distinct clinically relevant TIB subsets, laying a foundation for further exploration of functional commonality and diversity of B cells in cancer.
Subject(s)
Neoplasms , Single-Cell Analysis , Humans , Neoplasms/immunology , Neoplasms/pathology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Phenotype , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Immunotherapy , PrognosisABSTRACT
Natural killer (NK) cells play indispensable roles in innate immune responses against tumor progression. To depict their phenotypic and functional diversities in the tumor microenvironment, we perform integrative single-cell RNA sequencing analyses on NK cells from 716 patients with cancer, covering 24 cancer types. We observed heterogeneity in NK cell composition in a tumor-type-specific manner. Notably, we have identified a group of tumor-associated NK cells that are enriched in tumors, show impaired anti-tumor functions, and are associated with unfavorable prognosis and resistance to immunotherapy. Specific myeloid cell subpopulations, in particular LAMP3+ dendritic cells, appear to mediate the regulation of NK cell anti-tumor immunity. Our study provides insights into NK-cell-based cancer immunity and highlights potential clinical utilities of NK cell subsets as therapeutic targets.
Subject(s)
Killer Cells, Natural , Neoplasms , Tumor Microenvironment , Humans , Immunity, Innate , Immunotherapy , Killer Cells, Natural/immunology , Myeloid Cells , Neoplasms/immunology , Dendritic Cells/immunology , Single-Cell Gene Expression AnalysisABSTRACT
BACKGROUND: Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown. METHODS: The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2f/f; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2-/- cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts. RESULTS: PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2f/f; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2-/- cells and the renal cystogenesis of Tsc2f/f; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis. CONCLUSIONS: Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.
Subject(s)
Adaptor Proteins, Signal Transducing , MicroRNAs , Signal Transduction , TOR Serine-Threonine Kinases , Tuberous Sclerosis Complex 2 Protein , Tuberous Sclerosis , Animals , MicroRNAs/genetics , MicroRNAs/metabolism , TOR Serine-Threonine Kinases/metabolism , Tuberous Sclerosis/metabolism , Tuberous Sclerosis/genetics , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/metabolism , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/metabolism , Kidney Diseases, Cystic/pathology , Humans , Mice, Knockout , Disease Models, AnimalABSTRACT
Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.
Subject(s)
CD8-Positive T-Lymphocytes , Colorectal Neoplasms , Immunotherapy , Single-Cell Analysis , Humans , Colorectal Neoplasms/immunology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/therapy , Colorectal Neoplasms/pathology , Single-Cell Analysis/methods , CD8-Positive T-Lymphocytes/immunology , Immunotherapy/methods , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Lymphocytes, Tumor-Infiltrating/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Male , FemaleABSTRACT
Fibroblasts, known for their functional diversity, play crucial roles in inflammation and cancer. In this study, we conduct comprehensive single-cell RNA sequencing analyses on fibroblast cells from 517 human samples, spanning 11 tissue types and diverse pathological states. We identify distinct fibroblast subpopulations with universal and tissue-specific characteristics. Pathological conditions lead to significant shifts in fibroblast compositions, including the expansion of immune-modulating fibroblasts during inflammation and tissue-remodeling myofibroblasts in cancer. Within the myofibroblast category, we identify four transcriptionally distinct subpopulations originating from different developmental origins, with LRRC15+ myofibroblasts displaying terminally differentiated features. Both LRRC15+ and MMP1+ myofibroblasts demonstrate pro-tumor potential that contribute to the immune-excluded and immune-suppressive tumor microenvironments (TMEs), whereas PI16+ fibroblasts show potential anti-tumor functions in adjacent non-cancerous regions. Fibroblast-subtype compositions define patient subtypes with distinct clinical outcomes. This study advances our understanding of fibroblast biology and suggests potential therapeutic strategies for targeting specific fibroblast subsets in cancer treatment.