Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance

Sanne J de Haart, Niels W C J van de Donk, Monique C Minnema, Julie H Huang, Tineke Aarts-Riemens, Niels Bovenschen, Huipin Yuan, Richard W J Groen, Douglas W McMillin, Jana Jakubikova, Henk M Lokhorst, Anton C Martens, Constantine S Mitsiades, Tuna Mutis

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

PURPOSE: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.

EXPERIMENTAL DESIGN: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.

RESULTS: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.

CONCLUSION: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

Original languageEnglish
Pages (from-to)5591-601
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number20
DOIs
Publication statusPublished - 15 Oct 2013

Cite this

de Haart, Sanne J ; van de Donk, Niels W C J ; Minnema, Monique C ; Huang, Julie H ; Aarts-Riemens, Tineke ; Bovenschen, Niels ; Yuan, Huipin ; Groen, Richard W J ; McMillin, Douglas W ; Jakubikova, Jana ; Lokhorst, Henk M ; Martens, Anton C ; Mitsiades, Constantine S ; Mutis, Tuna. / Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 20. pp. 5591-601.
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title = "Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance",
abstract = "PURPOSE: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.EXPERIMENTAL DESIGN: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.RESULTS: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.CONCLUSION: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.",
keywords = "Animals, Antineoplastic Agents/therapeutic use, Cell Adhesion/immunology, Cell Communication, Cell Line, Tumor, Combined Modality Therapy, Cytotoxicity, Immunologic, Disease Models, Animal, Humans, Imidazoles/therapeutic use, Immunomodulation, Immunotherapy, Adoptive, Mice, Multiple Myeloma/immunology, Naphthoquinones/therapeutic use, T-Lymphocytes, Cytotoxic/immunology, Tumor Microenvironment/immunology, Xenograft Model Antitumor Assays, fas Receptor/metabolism",
author = "{de Haart}, {Sanne J} and {van de Donk}, {Niels W C J} and Minnema, {Monique C} and Huang, {Julie H} and Tineke Aarts-Riemens and Niels Bovenschen and Huipin Yuan and Groen, {Richard W J} and McMillin, {Douglas W} and Jana Jakubikova and Lokhorst, {Henk M} and Martens, {Anton C} and Mitsiades, {Constantine S} and Tuna Mutis",
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year = "2013",
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de Haart, SJ, van de Donk, NWCJ, Minnema, MC, Huang, JH, Aarts-Riemens, T, Bovenschen, N, Yuan, H, Groen, RWJ, McMillin, DW, Jakubikova, J, Lokhorst, HM, Martens, AC, Mitsiades, CS & Mutis, T 2013, 'Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance' Clinical Cancer Research, vol. 19, no. 20, pp. 5591-601. https://doi.org/10.1158/1078-0432.CCR-12-3676

Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance. / de Haart, Sanne J; van de Donk, Niels W C J; Minnema, Monique C; Huang, Julie H; Aarts-Riemens, Tineke; Bovenschen, Niels; Yuan, Huipin; Groen, Richard W J; McMillin, Douglas W; Jakubikova, Jana; Lokhorst, Henk M; Martens, Anton C; Mitsiades, Constantine S; Mutis, Tuna.

In: Clinical Cancer Research, Vol. 19, No. 20, 15.10.2013, p. 5591-601.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance

AU - de Haart, Sanne J

AU - van de Donk, Niels W C J

AU - Minnema, Monique C

AU - Huang, Julie H

AU - Aarts-Riemens, Tineke

AU - Bovenschen, Niels

AU - Yuan, Huipin

AU - Groen, Richard W J

AU - McMillin, Douglas W

AU - Jakubikova, Jana

AU - Lokhorst, Henk M

AU - Martens, Anton C

AU - Mitsiades, Constantine S

AU - Mutis, Tuna

N1 - ©2013 AACR.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - PURPOSE: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.EXPERIMENTAL DESIGN: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.RESULTS: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.CONCLUSION: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

AB - PURPOSE: Cellular immunotherapy frequently fails to induce sustained remissions in patients with multiple myeloma, indicating the ability of multiple myeloma cells to evade cellular immunity. Toward a better understanding and effective therapeutic modulation of multiple myeloma immune evasion mechanisms, we here investigated the role of the tumor microenvironment in rendering multiple myeloma cells resistant to the cytotoxic machinery of T cells.EXPERIMENTAL DESIGN: Using a compartment-specific, bioluminescence imaging-based assay system, we measured the lysis of luciferase-transduced multiple myeloma cells by CD4(+) or CD8(+) CTLs in the presence versus absence of adherent accessory cells of the bone marrow microenvironment. We simultaneously determined the level of CTL activation by measuring the granzyme B release in culture supernatants.RESULTS: Bone marrow stromal cells from patients with multiple myeloma and healthy individuals, as well as vascular endothelial cells, significantly inhibited the lysis of multiple myeloma cells in a cell-cell contact-dependent manner and without substantial T-cell suppression, thus showing the induction of a cell adhesion-mediated immune resistance (CAM-IR) against CTL lysis. Further analyses revealed that adhesion to accessory cells downregulated Fas and upregulated the caspase-3 inhibitor survivin in multiple myeloma cells. Reconstitution of Fas expression with bortezomib enhanced the CTL-mediated lysis of multiple myeloma cells. Repressing survivin with the small-molecule YM155 synergized with CTLs and abrogated CAM-IR in vitro and in vivo.CONCLUSION: These results reveal the cell adhesion-mediated induction of apoptosis resistance as a novel immune escape mechanism and provide a rationale to improve the efficacy of cellular therapies by pharmacologic modulation of CAM-IR.

KW - Animals

KW - Antineoplastic Agents/therapeutic use

KW - Cell Adhesion/immunology

KW - Cell Communication

KW - Cell Line, Tumor

KW - Combined Modality Therapy

KW - Cytotoxicity, Immunologic

KW - Disease Models, Animal

KW - Humans

KW - Imidazoles/therapeutic use

KW - Immunomodulation

KW - Immunotherapy, Adoptive

KW - Mice

KW - Multiple Myeloma/immunology

KW - Naphthoquinones/therapeutic use

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Tumor Microenvironment/immunology

KW - Xenograft Model Antitumor Assays

KW - fas Receptor/metabolism

U2 - 10.1158/1078-0432.CCR-12-3676

DO - 10.1158/1078-0432.CCR-12-3676

M3 - Article

VL - 19

SP - 5591

EP - 5601

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 20

ER -