Lossos, Chen, Liu, Yunpeng, Kolb, Kellie E., Christie, Amanda L., Van Scoyk, Alexandria ORCID: 0000-0001-6692-1062, Prakadan, Sanjay M., Shigemori, Kay ORCID: 0000-0002-9682-4164, Stevenson, Kristen E., Morrow, Sara, Plana, Olivia D., Fraser, Cameron, Jones, Kristen L., Liu, Huiyun, Pallasch, Christian P. ORCID: 0000-0001-5675-6905, Modiste, Rebecca, Craig, Jeffrey W., Morgan, Elizabeth A., Vega, Francisco ORCID: 0000-0001-5956-452X, Aster, Jon C., Sarosiek, Kristopher A., Shalek, Alex K., Hemann, Michael T. and Weinstock, David M. (2019). Mechanisms of Lymphoma Clearance Induced by High-Dose Alkylating Agents. Cancer Discov., 9 (7). S. 944 - 962. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lossos, ChenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, YunpengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolb, Kellie E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christie, Amanda L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Scoyk, AlexandriaUNSPECIFIEDorcid.org/0000-0001-6692-1062UNSPECIFIED
Prakadan, Sanjay M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shigemori, KayUNSPECIFIEDorcid.org/0000-0002-9682-4164UNSPECIFIED
Stevenson, Kristen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrow, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plana, Olivia D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fraser, CameronUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, Kristen L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, HuiyunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallasch, Christian P.UNSPECIFIEDorcid.org/0000-0001-5675-6905UNSPECIFIED
Modiste, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Craig, Jeffrey W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, Elizabeth A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, FranciscoUNSPECIFIEDorcid.org/0000-0001-5956-452XUNSPECIFIED
Aster, Jon C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarosiek, Kristopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shalek, Alex K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemann, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinstock, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-136525
DOI: 10.1158/2159-8290.CD-18-1393
Journal or Publication Title: Cancer Discov.
Volume: 9
Number: 7
Page Range: S. 944 - 962
Date: 2019
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MONOCLONAL-ANTIBODY; BURKITTS-LYMPHOMA; ER STRESS; CELLS; RESISTANCE; PHAGOCYTOSIS; MACROPHAGES; RECEPTOR; THERAPY; IMMUNOPHENOTYPEMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/13652

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