Data from Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis Article Swipe
Lisa C. Holthof
,
Jort J. van der Schans
,
Afroditi Katsarou
,
Renée Poels
,
Anne T. Gelderloos
,
Esther Drent
,
Susan E. van Hal-van Veen
,
Fengzhi Li
,
Sonja Zweegman
,
Niels W.C.J. van de Donk
,
Maria Themeli
,
Richard W.J. Groen
,
Tuna Mutis
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6530726
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.c.6530726
Purpose:The microenvironment of multiple myeloma (MM) can critically impair therapy outcome, including immunotherapies. In this context, we have earlier demonstrated that bone marrow mesenchymal stromal cells (BMMSC) protect MM cells against the lytic machinery of MM-reactive cytotoxic T cells (CTL) and daratumumab-redirected natural killer (NK) cells through the upregulation of antiapoptotic proteins Survivin and Mcl-1 in MM cells. Here, we investigated the significance of this mode of immune escape on T cells engineered to express chimeric antigen receptors (CAR T cells).Experimental Design:We tested the cytolytic ability of a panel of 10 BCMA-, CD38-, and CD138-specific CAR T cells with different affinities against a model MM cell line and against patient-derived MM cells in the presence versus absence of BMMSCs.Results:Although BMMSCs hardly protected MM cells from lysis by high-affinity, strongly lytic BCMA- and CD38-CAR T cells, they significantly protected against lower affinity, moderately lytic BCMA-, CD38-, and CD138-specific CAR T cells in a cell–cell contact-dependent manner. Overall, there was a remarkable inverse correlation between the protective ability of BMMSCs and the lytic activity of all CAR T cells, which was dependent on CAR affinity and type of costimulation. Furthermore, BMMSC-mediated resistance against CAR T cells was effectively modulated by FL118, an inhibitor of antiapoptotic proteins Survivin, Mcl-1, and XIAP.Conclusions:These results extend our findings on the negative impact of the microenvironment against immunotherapies and suggest that outcome of CAR T cell or conventional CTL therapies could benefit from inhibition of antiapoptotic proteins upregulated in MM cells through BMMSC interactions.
Related Topics
Concepts
Cytotoxic T cell
CD38
Stromal cell
Cancer research
Bone marrow
Chimeric antigen receptor
Lytic cycle
Biology
Molecular biology
Immunology
Immune system
Chemistry
T cell
Cell biology
In vitro
CD34
Stem cell
Biochemistry
Virus
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1158/1078-0432.c.6530726
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4361947407
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4361947407Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1158/1078-0432.c.6530726Digital Object Identifier
- Title
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Data from Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of ApoptosisWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-03-31Full publication date if available
- Authors
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Lisa C. Holthof, Jort J. van der Schans, Afroditi Katsarou, Renée Poels, Anne T. Gelderloos, Esther Drent, Susan E. van Hal-van Veen, Fengzhi Li, Sonja Zweegman, Niels W.C.J. van de Donk, Maria Themeli, Richard W.J. Groen, Tuna MutisList of authors in order
- Landing page
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https://doi.org/10.1158/1078-0432.c.6530726Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.1158/1078-0432.c.6530726Direct OA link when available
- Concepts
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Cytotoxic T cell, CD38, Stromal cell, Cancer research, Bone marrow, Chimeric antigen receptor, Lytic cycle, Biology, Molecular biology, Immunology, Immune system, Chemistry, T cell, Cell biology, In vitro, CD34, Stem cell, Biochemistry, VirusTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.(NK) | 44 |
| abstract_inverted_index.bone | 21 |
| abstract_inverted_index.cell | 105, 228 |
| abstract_inverted_index.from | 124, 235 |
| abstract_inverted_index.have | 17 |
| abstract_inverted_index.line | 106 |
| abstract_inverted_index.mode | 65 |
| abstract_inverted_index.that | 20, 223 |
| abstract_inverted_index.they | 135 |
| abstract_inverted_index.this | 14, 64 |
| abstract_inverted_index.type | 184 |
| abstract_inverted_index.with | 98 |
| abstract_inverted_index.(CTL) | 39 |
| abstract_inverted_index.BCMA- | 130 |
| abstract_inverted_index.BMMSC | 245 |
| abstract_inverted_index.Here, | 58 |
| abstract_inverted_index.Mcl-1 | 54 |
| abstract_inverted_index.cells | 25, 29, 38, 45, 71, 97, 111, 123, 149, 193, 243 |
| abstract_inverted_index.could | 233 |
| abstract_inverted_index.lower | 139 |
| abstract_inverted_index.lysis | 125 |
| abstract_inverted_index.lytic | 32, 129, 142, 170 |
| abstract_inverted_index.model | 103 |
| abstract_inverted_index.panel | 88 |
| abstract_inverted_index.there | 156 |
| abstract_inverted_index.which | 177 |
| abstract_inverted_index.BCMA-, | 91, 143 |
| abstract_inverted_index.BMMSCs | 119, 167 |
| abstract_inverted_index.CD38-, | 92, 144 |
| abstract_inverted_index.FL118, | 198 |
| abstract_inverted_index.Mcl-1, | 205 |
| abstract_inverted_index.cells, | 134, 176 |
| abstract_inverted_index.cells. | 57 |
| abstract_inverted_index.escape | 68 |
| abstract_inverted_index.extend | 209 |
| abstract_inverted_index.hardly | 120 |
| abstract_inverted_index.immune | 67 |
| abstract_inverted_index.impact | 215 |
| abstract_inverted_index.impair | 8 |
| abstract_inverted_index.killer | 43 |
| abstract_inverted_index.marrow | 22 |
| abstract_inverted_index.tested | 82 |
| abstract_inverted_index.versus | 115 |
| abstract_inverted_index.(BMMSC) | 26 |
| abstract_inverted_index.ability | 85, 165 |
| abstract_inverted_index.absence | 116 |
| abstract_inverted_index.against | 30, 101, 108, 138, 190, 219 |
| abstract_inverted_index.antigen | 76 |
| abstract_inverted_index.benefit | 234 |
| abstract_inverted_index.between | 162 |
| abstract_inverted_index.earlier | 18 |
| abstract_inverted_index.express | 74 |
| abstract_inverted_index.inverse | 160 |
| abstract_inverted_index.manner. | 154 |
| abstract_inverted_index.myeloma | 4 |
| abstract_inverted_index.natural | 42 |
| abstract_inverted_index.outcome | 224 |
| abstract_inverted_index.protect | 27 |
| abstract_inverted_index.results | 208 |
| abstract_inverted_index.stromal | 24 |
| abstract_inverted_index.suggest | 222 |
| abstract_inverted_index.therapy | 9 |
| abstract_inverted_index.through | 46, 244 |
| abstract_inverted_index.CD38-CAR | 132 |
| abstract_inverted_index.Overall, | 155 |
| abstract_inverted_index.Survivin | 52 |
| abstract_inverted_index.activity | 171 |
| abstract_inverted_index.affinity | 182 |
| abstract_inverted_index.chimeric | 75 |
| abstract_inverted_index.context, | 15 |
| abstract_inverted_index.findings | 211 |
| abstract_inverted_index.multiple | 3 |
| abstract_inverted_index.negative | 214 |
| abstract_inverted_index.outcome, | 10 |
| abstract_inverted_index.presence | 114 |
| abstract_inverted_index.proteins | 51, 203, 239 |
| abstract_inverted_index.strongly | 128 |
| abstract_inverted_index.Survivin, | 204 |
| abstract_inverted_index.affinity, | 140 |
| abstract_inverted_index.cytolytic | 84 |
| abstract_inverted_index.cytotoxic | 36 |
| abstract_inverted_index.dependent | 179 |
| abstract_inverted_index.different | 99 |
| abstract_inverted_index.including | 11 |
| abstract_inverted_index.inhibitor | 200 |
| abstract_inverted_index.machinery | 33 |
| abstract_inverted_index.modulated | 196 |
| abstract_inverted_index.protected | 121, 137 |
| abstract_inverted_index.receptors | 77 |
| abstract_inverted_index.therapies | 232 |
| abstract_inverted_index.affinities | 100 |
| abstract_inverted_index.critically | 7 |
| abstract_inverted_index.engineered | 72 |
| abstract_inverted_index.inhibition | 236 |
| abstract_inverted_index.moderately | 141 |
| abstract_inverted_index.protective | 164 |
| abstract_inverted_index.remarkable | 159 |
| abstract_inverted_index.resistance | 189 |
| abstract_inverted_index.MM-reactive | 35 |
| abstract_inverted_index.cell–cell | 152 |
| abstract_inverted_index.correlation | 161 |
| abstract_inverted_index.effectively | 195 |
| abstract_inverted_index.mesenchymal | 23 |
| abstract_inverted_index.upregulated | 240 |
| abstract_inverted_index.Furthermore, | 187 |
| abstract_inverted_index.conventional | 230 |
| abstract_inverted_index.demonstrated | 19 |
| abstract_inverted_index.investigated | 60 |
| abstract_inverted_index.significance | 62 |
| abstract_inverted_index.upregulation | 48 |
| abstract_inverted_index.antiapoptotic | 50, 202, 238 |
| abstract_inverted_index.significantly | 136 |
| abstract_inverted_index.BMMSC-mediated | 188 |
| abstract_inverted_index.CD138-specific | 94, 146 |
| abstract_inverted_index.costimulation. | 186 |
| abstract_inverted_index.high-affinity, | 127 |
| abstract_inverted_index.immunotherapies | 220 |
| abstract_inverted_index.patient-derived | 109 |
| abstract_inverted_index.immunotherapies. | 12 |
| abstract_inverted_index.microenvironment | 1, 218 |
| abstract_inverted_index.contact-dependent | 153 |
| abstract_inverted_index.Design:<p>We | 81 |
| abstract_inverted_index.daratumumab-redirected | 41 |
| abstract_inverted_index.cells).</p>Experimental | 80 |
| abstract_inverted_index.interactions.</p></div> | 246 |
| abstract_inverted_index.<div>AbstractPurpose:<p>The | 0 |
| abstract_inverted_index.XIAP.</p>Conclusions:<p>These | 207 |
| abstract_inverted_index.BMMSCs.</p>Results:<p>Although | 118 |
| cited_by_percentile_year | |
| countries_distinct_count | 0 |
| institutions_distinct_count | 13 |
| citation_normalized_percentile.value | 0.17550856 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |