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 1

CD226 limits spontaneous MM progression.

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CD226 limits spontaneous MM progression. (A–C) C57BL/6 Cd226+/+ (n = 55)...
(A–C) C57BL/6 Cd226+/+ (n = 55), Cd226–/+ (n = 27), and Cd226–/– (n = 25) Vk*MYC transgenic mice, along with Cd226+/+ (n = 12), Cd226–/+ (n = 15), and Cd226–/– (n = 9) nontransgenic littermate controls, were monitored for MM development (A and B) and survival (C). (A and B) Cd226–/– Vk*MYC mice have higher γ-globulin levels. (A) Graph showing the mean γ-globulin levels ± SEM in the serum of the indicated strains of mice over time. (B) Representative SPEP of Cd226+/+ and Cd226–/– Vk*MYC transgenic mice after 500 days. Arrows indicate M-spike. (C) Kaplan Meyer curves showing a significant decrease in the survival of Cd226–/– Vk*MYC mice as compared to WT and Cd226–/+ Vk*MYC littermates. (D–F) Cd226–/– Vk*MYC transgenic mice have an increased frequency of malignant PCs expressing CD155 in the BM. The percentage and the number of malignant PCs and their level of CD155 expression were analyzed by FACS in the BM of Cd226+/+ (n = 15) and Cd226–/– (n = 14) Vk*MYC transgenic mice and in Cd226+/+ (n = 6) and Cd226–/– (n = 10) nontransgenic littermate controls. (D and E) Graphs (D) and representative FACS plots (E) showing the mean frequency and number ± SEM of CD138+CD155+ malignant PCs in the BM of the indicated strains of mice at 450 days of age. (F) Graph showing similar level of CD155 expression on B220–CD138+ BM PCs from Cd226–/– Vk*MYC and Cd226+/+ Vk*MYC mice. Each symbol represents 1 individual mouse. *P < 0.05, **P < 0.01, ***P < 0.001; Mann-Whitney U test (A and D) Mantel-Cox test (C).