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Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents
- Source :
- PMC
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
Abstract
- The extraordinary activity of high-dose cyclophosphamide against some high-grade lymphomas was described nearly 60 years ago. Here we address mechanisms that mediate cyclophosphamide activity in bona fide human double-hit lymphoma. We show that antibody resistance within the bone marrow (BM) is not present upon early engraftment but develops during lymphoma progression. This resistance required a high tumor:macrophage ratio, was recapitulated in spleen by partial macrophage depletion, and was overcome by multiple, high-dose alkylating agents. Cyclophosphamide induced endoplasmic reticulum (ER) stress in BM-resident lymphoma cells in vivo that resulted in ATF4-mediated paracrine secretion of VEGFA, massive macrophage infiltration, and clearance of alemtuzumab-opsonized cells. BM macrophages isolated after cyclophosphamide treatment had increased phagocytic capacity that was reversed by VEGFA blockade or SYK inhibition. Single-cell RNA sequencing of these macrophages identified a “super-phagocytic” subset that expressed CD36/FCGR4. Together, these findings define a novel mechanism through which high-dose alkylating agents promote macrophage-dependent lymphoma clearance. Significance: mAbs are effective against only a small subset of cancers. Herein, we recapitulate compartment-specific antibody resistance and define an ER stress–dependent mechanism induced by high-dose alkylating agents that promotes phagocytosis of opsonized tumor cells. This approach induces synergistic effects with mAbs and merits testing across additional tumor types. See related commentary by Duval and De Palma, p. 834. This article is highlighted in the In This Issue feature, p. 813
- Subjects :
- 0301 basic medicine
Alkylating Agents
Lymphoma, B-Cell
Cyclophosphamide
Phagocytosis
Syk
Mice, SCID
Mice
Random Allocation
03 medical and health sciences
0302 clinical medicine
Bone Marrow
Mice, Inbred NOD
Cell Line, Tumor
medicine
Animals
Humans
Macrophage
Alemtuzumab
Dose-Response Relationship, Drug
biology
Chemistry
Macrophages
Antibodies, Monoclonal
Endoplasmic Reticulum Stress
medicine.disease
Xenograft Model Antitumor Assays
Lymphoma
Vascular endothelial growth factor A
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Cancer research
biology.protein
Bone marrow
Antibody
medicine.drug
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....56896653a7f18d14ffcefe45c7d6ac86