Bone Marrow Mesenchymal Stromal Cells Can Render Multiple Myeloma Cells Resistant to Cytotoxic Machinery of CAR T Cells through Inhibition of Apoptosis
| Autor: | Susan E. van Hal-van Veen, Anne T. Gelderloos, Maria Themeli, Fengzhi Li, Renée Poels, Tuna Mutis, Jort J. van der Schans, Sonja Zweegman, Lisa C. Holthof, Richard W.J. Groen, Afroditi Katsarou, Niels W.C.J. van de Donk, Esther Drent |
|---|---|
| Přispěvatelé: | VU University medical center, Hematology, AII - Cancer immunology, CCA - Cancer biology and immunology, Hematology laboratory |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Apoptosis CD38 Immunotherapy Adoptive 03 medical and health sciences 0302 clinical medicine Survivin Tumor Cells Cultured medicine Humans Cytotoxic T cell Receptors Chimeric Antigen Chemistry Mesenchymal stem cell Mesenchymal Stem Cells Chimeric antigen receptor CTL 030104 developmental biology medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Bone marrow Multiple Myeloma T-Lymphocytes Cytotoxic |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research, 27(13), 3793-3803. American Association for Cancer Research Inc. Holthof, L C, van der Schans, J J, Katsarou, A, Poels, R, Gelderloos, A T, Drent, E, van Hal-van Veen, S E, Li, F, Zweegman, S, van de Donk, N W C J, Themeli, M, Groen, R W J & Mutis, T 2021, ' Bone marrow mesenchymal stromal cells can render multiple myeloma cells resistant to cytotoxic machinery of CAR T cells through inhibition of apoptosis ', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 27, no. 13, pp. 3793-3803 . https://doi.org/10.1158/1078-0432.CCR-20-2188 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-20-2188 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|