RESUMEN
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.
Asunto(s)
Neoplasias , Análisis de la Célula Individual , Humanos , Neoplasias/inmunología , Neoplasias/patología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Fenotipo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Inmunoterapia , PronósticoRESUMEN
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.
Asunto(s)
Células Asesinas Naturales , Neoplasias , Microambiente Tumoral , Humanos , Inmunidad Innata , Inmunoterapia , Células Asesinas Naturales/inmunología , Células Mieloides , Neoplasias/inmunología , Células Dendríticas/inmunología , Análisis de Expresión Génica de una Sola CélulaRESUMEN
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.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias Colorrectales , Inmunoterapia , Análisis de la Célula Individual , Humanos , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patología , Análisis de la Célula Individual/métodos , Linfocitos T CD8-positivos/inmunología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Masculino , FemeninoRESUMEN
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.