Summary

Brain tumors are typically immunosuppressive and refractory to immunotherapies for reasons that remain poorly understood. The unbiased profiling of immune cell types in the tumor microenvironment may reveal immunologic networks affecting therapy and course of disease. Here we identify and validate the presence of hematopoietic stem and progenitor cells (HSPCs) within glioblastoma tissues. Furthermore, we demonstrate a positive link of tumor-associated HSPCs with malignant and immunosuppressive phenotypes. Compared to the medullary hematopoietic compartment, tumor-associated HSPCs contain a higher fraction of immunophenotypically and transcriptomically immature, CD38- cells, such as hematopoietic stem cells and multipotent progenitors, express genes related to glioblastoma progression and display signatures of active cell cycle phases. When cultured ex vivo, tumor-associated HSPCs form myeloid colonies, suggesting potential in situ myelopoiesis. In experimental models, HSPCs promote tumor cell proliferation, expression of the immune checkpoint PD-L1 and secretion of tumor promoting cytokines such as IL-6, IL-8 and CCL2, indicating concomitant support of both malignancy and immunosuppression. In patients, the amount of tumor-associated HSPCs in tumor tissues is prognostic for patient survival and correlates with immunosuppressive phenotypes. These findings identify an important element in the complex landscape of glioblastoma that may serve as a target for brain tumor immunotherapies.

Overall design

Examination of single-cell transcriptomics from tumor-associated HSPCs and canonical HSPC

Contributors

I-Na Lu # 1 2 3, Celia Dobersalske # 1 2 3, Laurèl Rauschenbach 1 3 4, Sarah Teuber-Hanselmann 5, Anita Steinbach 1 2 3, Vivien Ullrich 1 2 3, Shruthi Prasad 1 2 3, Tobias Blau 5, Sied Kebir 1 3 6, Jens T Siveke 2 3 7 8, Jürgen C Becker 2 3 9, Ulrich Sure 3 4, Martin Glas 1 3 6, Björn Scheffler 1 2 3 10, Igor Cima 11 12 13

Contact

i.cima@dkfz.de.(Igor Cima)