Immunosurveillance and therapy of multiple myeloma are CD226 dependent
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
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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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 4

Progressive immunosuppression is associated with myeloma progression in vivo.

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Progressive immunosuppression is associated with myeloma progression in ...
(A and B) Representative FACS plots (A) and graphs (B) showing the percentages of TCRβ+CD8+ cells and NK1.1+TCRβ– NK cells in the peripheral blood of Cd226+/+ Vk*MYC mice (n = 20) and nontransgenic control mice (n = 7) at 600 and 700 days. (C) Graphs showing the numbers of TCRβ+CD8+ cells and NK1.1+TCRβ– NK cells in the BM of naive mice or mice injected with Vk12653 MM cells for 5 weeks. Representative experiment out of 2 involving groups of n = 5–10 mice. (D) Graphs showing the correlation between the percentage of NK and CD8+ T cells and the number of BM PCs in the BM of mice injected with Vk12653 cells for 5 weeks (n = 61). Pearson r coefficient and associated P values are shown. (E) Graphs showing the mean fluorescence intensity (MFI) of CD226 on CD8+ T cells and NK cells as in A. (F) Representative histogram plots and graphs showing the MFI of CD226 staining on NK cells and CD8+ T cells as in C. Isotype control staining (gray line), and CD226 staining on naive mice (black line) and MM-bearing mice (dotted line) are shown. (G) Graph showing the correlation between the expression of CD226 on NK cells and CD8+ T cells and the number of BM PCs in the BM of mice injected with Vk12653 cells for 5 weeks (n = 20). Pearson r coefficient and associated P values are shown. Each symbol represents 1 individual mouse. *P < 0.05, **P < 0.01, ***P < 0.001; paired Student’s t test (B and E) and Mann-Whitney U test (C and F).