Immunosurveillance and therapy of multiple myeloma are CD226 dependent
Camille Guillerey, … , Mark J. Smyth, Ludovic Martinet
Camille Guillerey, … , Mark J. Smyth, Ludovic Martinet
Published April 20, 2015
Citation Information: J Clin Invest. 2015;125(5):2077-2089. https://doi.org/10.1172/JCI77181.
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Research Article Immunology Oncology

Immunosurveillance and therapy of multiple myeloma are CD226 dependent

Abstract

Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment. We monitored Vk*MYC mice that had been crossed with Cd226 mutant mice over a period of 3 years and found that CD226 limits spontaneous MM development. The CD226-dependent anti-myeloma immune response against transplanted Vk*MYC MM cells was mediated both by NK and CD8+ T cells through perforin and IFN-γ pathways. Moreover, CD226 expression was required for optimal antimyeloma efficacy of cyclophosphamide (CTX) and bortezomib (Btz), which are both standardly used to manage MM in patients. Activation of costimulatory receptor CD137 with mAb (4-1BB) exerted strong antimyeloma activity, while inhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect. Taken together, the results of this study provide in vivo evidence that CD226 is important for MM immunosurveillance and indicate that specific immune components should be targeted for optimal MM treatment efficacy. As progressive immunosuppression associates with MM development, strategies aimed to increase immune functions may have important therapeutic implications in MM.

Authors

Camille Guillerey, Lucas Ferrari de Andrade, Slavica Vuckovic, Kim Miles, Shin Foong Ngiow, Michelle C.R. Yong, Michele W.L. Teng, Marco Colonna, David S. Ritchie, Martha Chesi, P. Leif Bergsagel, Geoffrey R. Hill, Mark J. Smyth, Ludovic Martinet

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Figure 3

Critical role for NK and CD8+ T cells in the control MM through perforin and interferon-γ pathways.

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Critical role for NK and CD8+ T cells in the control MM through perforin...
(A) NK cells and CD8+ T cells limit Vk*MYC MM burden in vivo. WT mice were injected with control IgG, anti-AsGM1 and/or anti-CD8β to deplete NK cells and/or CD8+ T cells, and were challenged with Vk12653 cells. The γ-globulin levels in the serum of the indicated groups of mice 3 weeks after injection, and the percentages and numbers of CD138+B220– PCs in the BM and in the spleen (SPL) of the indicated groups of mice are shown. Representative experiment out of 2 involving groups of n = 10 mice. (B–D) WT, Pfp–/–, and Ifng–/– mice were injected i.v. with 2 × 106 Vk12653 cells. (B) MM burden was evaluated by SPEP 1, 3, and 5 weeks after injection. The γ-globulin levels in the serum of the indicated groups of mice are shown. (C and D) the percentages and numbers of CD138+B220– PCs in the BM (C) and in the SPL (D) of the indicated groups of mice are shown. Representative experiment out of 2 involving groups of n = 10 mice. (E and F) WT, Pfp–/–, and Ifng–/– mice were injected i.v. with 5 × 105 Vk12653 cells (E) or 4 × 105 Vk12598 cells (F), and the survival of mice was analyzed after injection. Groups of n = 10 mice are shown. Each symbol represents 1 individual mouse. *P < 0.05, **P < 0.01, ***P < 0.001; Mann-Whitney U test (A–D) and Mantel-Cox test (E and F).