Mechanisms of lymphoma clearance induced by high-dose alkylating agents
© 2019 American Association for Cancer Research. 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 antibo...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for Cancer Research (AACR)
2021
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| Online Access: | https://hdl.handle.net/1721.1/136179 |
| _version_ | 1826193334007234560 |
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| author | Lossos, Chen Liu, Yunpeng Kolb, Kellie E Christie, Amanda L van Scoyk, Alexandria Prakadan, Sanjay M Shigemori, Kay Stevenson, Kristen E Morrow, Sara Plana, Olivia D Fraser, Cameron Jones, Kristen L Liu, Huiyun Pallasch, Christian P Modiste, Rebecca Nguyen, Quang-De Craig, Jeffrey W Morgan, Elizabeth A Vega, Francisco Aster, Jon C Sarosiek, Kristopher A Shalek, Alex K Hemann, Michael T Weinstock, David M |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Lossos, Chen Liu, Yunpeng Kolb, Kellie E Christie, Amanda L van Scoyk, Alexandria Prakadan, Sanjay M Shigemori, Kay Stevenson, Kristen E Morrow, Sara Plana, Olivia D Fraser, Cameron Jones, Kristen L Liu, Huiyun Pallasch, Christian P Modiste, Rebecca Nguyen, Quang-De Craig, Jeffrey W Morgan, Elizabeth A Vega, Francisco Aster, Jon C Sarosiek, Kristopher A Shalek, Alex K Hemann, Michael T Weinstock, David M |
| author_sort | Lossos, Chen |
| collection | MIT |
| description | © 2019 American Association for Cancer Research. 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. |
| first_indexed | 2024-09-23T09:37:24Z |
| format | Article |
| id | mit-1721.1/136179 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:37:24Z |
| publishDate | 2021 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1361792024-03-20T19:08:17Z Mechanisms of lymphoma clearance induced by high-dose alkylating agents Lossos, Chen Liu, Yunpeng Kolb, Kellie E Christie, Amanda L van Scoyk, Alexandria Prakadan, Sanjay M Shigemori, Kay Stevenson, Kristen E Morrow, Sara Plana, Olivia D Fraser, Cameron Jones, Kristen L Liu, Huiyun Pallasch, Christian P Modiste, Rebecca Nguyen, Quang-De Craig, Jeffrey W Morgan, Elizabeth A Vega, Francisco Aster, Jon C Sarosiek, Kristopher A Shalek, Alex K Hemann, Michael T Weinstock, David M Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Ragon Institute of MGH, MIT and Harvard © 2019 American Association for Cancer Research. 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. 2021-10-27T20:34:07Z 2021-10-27T20:34:07Z 2019 2020-07-20T15:35:16Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136179 en 10.1158/2159-8290.CD-18-1393 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Lossos, Chen Liu, Yunpeng Kolb, Kellie E Christie, Amanda L van Scoyk, Alexandria Prakadan, Sanjay M Shigemori, Kay Stevenson, Kristen E Morrow, Sara Plana, Olivia D Fraser, Cameron Jones, Kristen L Liu, Huiyun Pallasch, Christian P Modiste, Rebecca Nguyen, Quang-De Craig, Jeffrey W Morgan, Elizabeth A Vega, Francisco Aster, Jon C Sarosiek, Kristopher A Shalek, Alex K Hemann, Michael T Weinstock, David M Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title | Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title_full | Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title_fullStr | Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title_full_unstemmed | Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title_short | Mechanisms of lymphoma clearance induced by high-dose alkylating agents |
| title_sort | mechanisms of lymphoma clearance induced by high dose alkylating agents |
| url | https://hdl.handle.net/1721.1/136179 |
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