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 Therapeutics

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 5

Optimal antimyeloma therapy requires CD226.

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Optimal antimyeloma therapy requires CD226. (A–E) The therapeutic effica...
(A–E) The therapeutic efficacy of Btz and CTX is altered in the absence of CD226. (A–D) WT and Cd226–/– mice were injected i.v. with 2 × 106 Vk12653 MM cells. After 3 weeks (indicated by arrows), mice were injected either with IgG or anti-CD226 mAbs and were subsequently treated with vehicle (PBS), Btz (i.p.; 0.5 mg/kg), or CTX (i.p.; 50 mg/kg) twice a week. (A and B) Serum paraproteinemia was analyzed every week by SPEP. Graphs showing the mean γ-globulin percentages ± SEM in the indicated groups of mice over time (A) and after 3 weeks of treatment (B). (C and D) Representative FACS plot showing the percentages (C) and graphs showing the numbers (D) of malignant CD138+CD155+ PCs in the BM of the indicated groups of mice at the end of the treatment. Data are pooled from 2 independent experiments involving 9 groups of n = 9–12 mice. Each symbol represents 1 individual mouse. (E) WT and Cd226–/– mice were injected i.v. with 4 × 105 Vk12598 MM cells. After 1 week, mice were treated with PBS or Btz (i.p.; 0.5 mg/kg) twice a week for 4 weeks, and the survival of the indicated groups of mice was monitored. Experiment involving groups of n = 10 mice. *P < 0.05, **P < 0.01, ***P < 0.001; Mann-Whitney U test (A, B, and D) and Mantel-Cox test (E).