Macrophage-tumor cell interaction promotes ATRT progression and chemoresistance

Abstract

Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and single-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68 + cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients' survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68 + macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and potentially to tumor recurrence.

Macrophages in SHH subgroup medulloblastoma display dynamic heterogeneity that varies with treatment modality

“…TAMs can also produce factors that promote tumor growth, angiogenesis, and metastasis (Lee et al, 2018;Maximov et al, 2019). Studies in many types of solid tumors show that TAMs are heterogeneous and their composition varies among tumors (Alshetaiwi et al, 2020;Gubin et al, 2018;Melcher et al, 2020). Despite increasing interest in TAMs as therapeutic targets, most studies have been performed on tumors outside the brain.…”

“…Finally, we wished to compare our scRNA-seq findings to another brain tumor model, selecting scRNA-seq data from a mouse model of an atypical teratoid rhabdoid tumor (ATRT) (Melcher et al, 2020). Like MB, ATRT is an embryonal tumor.…”

Ocoxin as a complement to first line treatments in cancer

“…This chemoresistance may be produced by the tumor host factors [103] or factors associated with tumor-tumor microenvironment interactions [104]. The implication of the tumor microenvironment on the progression of the tumor and the chemoresistance nowadays is widely recognized [105][106][107][108][109][110]. The tumor microenvironment consists of tumor cells, vasculature, extracellular matrix (ECM), non-malignant cells, such as, stromal cells, tumor associated fibroblast (CAFs), immune cells and a complex signaling molecule network which include growth factors, cytokines, chemokines, and exosomes that sustain the internal connections of the microenvironment, [111,112].…”

CAR T Cell Therapy for Pediatric Brain Tumors

“…Similar to other pediatric tumors, the immune infiltrate composition corresponds with the molecular subtype. Macrophages predominantly infiltrate the ATRT-SHH and ATRT-MYC subtypes and correlate with poor prognosis and treatment resistance ( 109 ). These data again indicate that therapeutic strategies must take into account the subtype classification and its respective immune microenvironment properties in pediatric brain tumors.…”