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Cancer Discov. 2019 Jul;9(7):944-961. doi: 10.1158/2159-8290.CD-18-1393. Epub 2019 Apr 30.

Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents.

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Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
Broad Institute of MIT and Harvard University, Cambridge, Massachusetts.
MIT Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts.
Institute for Medical Engineering and Science (IMES), Department of Chemistry, and Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts.
John B. Little Center for Radiation Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Division of Hematopathology, Department of Pathology and Laboratory Medicine, University of Miami/Sylvester Comprehensive Cancer Center, Miami, Florida.
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.


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.

[Available on 2020-07-01]

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