Glioblastoma induces the recruitment and differentiation of dendritic-like "hybrid" neutrophils from skull bone marrow.

in Cancer cell by Meeki Lad, Angad S Beniwal, Saket Jain, Poojan Shukla, Venina Kalistratova, Jangham Jung, Sumedh S Shah, Garima Yagnik, Atul Saha, Ankita Sati, Husam Babikir, Alan T Nguyen, Sabraj Gill, Jennifer Rios, Jacob S Young, Austin Lui, Diana Salha, Aaron Diaz, Manish K Aghi

TLDR

  • The study investigates the role of neutrophils in the immune response to brain tumors. The researchers found that neutrophils with dendritic features accumulate in the tumor and suppress its growth. They also identified a type of neutrophil that arises from local precursors and contributes to the immune response. The study highlights the potential of drugs that increase the number of neutrophils in the brain to treat brain tumors.

Abstract

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this "hybrid" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.

Overview

  • The study investigates the effects of tumor-associated neutrophils (TANs) on glioblastoma (GBM) biology. The hypothesis being tested is that neutrophils with dendritic features accumulate intratumorally and suppress tumor growth in vivo. The methodology used for the experiment includes scRNA-seq analysis of patient TANs, mouse models of GBM, and in vivo studies using labeled skull flaps and targeted ablation. The primary objective of the study is to identify the polarization state of hybrid dendritic-neutrophil phenotype and its contribution to antitumoral myeloid antigen-presenting cells (APCs) in GBM.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, including scRNA-seq analysis of patient TANs, mouse models of GBM, and in vivo studies using labeled skull flaps and targeted ablation. The results show that neutrophils with dendritic features accumulate intratumorally and suppress tumor growth in vivo. The study identifies a polarization state of hybrid dendritic-neutrophil phenotype that differentiates from canonical cytotoxic TANs and arises from local precursors. The study also characterizes calvarial marrow as a contributor of antitumoral myeloid APCs, including TANs, which elicit T cell cytotoxicity and memory.

Implications and Future Directions

  • The study's findings suggest that neutrophils with dendritic features play a crucial role in the antitumoral immune response in GBM. The study identifies calvarial marrow as a contributor of antitumoral myeloid APCs, including TANs, which elicit T cell cytotoxicity and memory. The study also highlights the potential of agents augmenting neutrophil egress from skull marrow, such as intracalvarial AMD3100, as therapeutic potential in GBM. Future research directions could include further investigation of the role of calvarial marrow in GBM and the development of targeted therapies to enhance neutrophil egress from this site.
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