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 6

Therapeutic efficacy of anti-CD137 immunotherapy against myeloma.

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Therapeutic efficacy of anti-CD137 immunotherapy against myeloma. (A and...
(A and B) WT mice were injected with cIg, anti-CD137, anti–PD-1, or anti–CTLA-4 and subsequently challenged with 2 × 106 Vk12653 MM cells. Representative FACS plot showing the percentages (A) and graphs showing the numbers (B) of CD138+CD155+ PCs in the BM at the end of the treatment. Data are representative of 2 independent experiments involving groups of n = 10 mice. (C–F) WT mice were injected i.v. with 2 × 106 Vk12653 MM cells. After 3 weeks, mice were injected either with IgG or anti-CD137 mAbs. Representative FACS plot and graph showing the percentages (C), the mean γ-globulin percentages (D), the mean numbers ± SEM of malignant CD138+CD155+ PCs in the BM (E) and the survival (F) of the indicated groups of mice. Each symbol represents 1 individual mouse. (G) WT mice were injected i.v. with 4 × 105 Vk12598 MM cells. After 1 week, mice were treated with IgG or anti-CD137 mAb twice a week for 4 weeks, and their survival was monitored. Experiment involving groups of n = 10 mice. (H) WT and Cd226–/– mice were injected i.v. with 2 × 106 Vk12653 MM cells. After 3 weeks, mice were injected either with IgG or anti-CD226 mAb and were subsequently treated with cIg or anti-CD137. Graphs show the percentages and the mean numbers ± SEM of malignant CD138+CD155+ PCs in the BM at the end of the treatment. Data are pooled from 2 independent experiments. **P < 0.01, ***P < 0.001, ****P < 0.0001; Mann-Whitney U test (B, D, E, and H) and Mantel-Cox test (F and G).