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 2

The interaction between CD226 and tumor CD155 is required for the immune-control of MM.

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The interaction between CD226 and tumor CD155 is required for the immune...
(A–C) WT or Cd226–/– mice were challenged i.v. with 2 × 106 Vk12653 cells. (A) Representative SPEP and graph showing the mean γ-globulin level ± SEM in the serum of the indicated strain of mice. Arrows indicate M-spike. (B) Representative FACS plots showing the frequency of CD138+B220– PCs in the BM and the spleen 5 weeks after injection. (C) Graphs showing the mean number of PCs in the BM and the spleen. Representative experiment out of 4 involving groups of n = 10 mice. (D and E) WT or Cd226–/– mice were challenged i.v. with 4 × 105 Vk12598 MM cells. Graphs showing the percentage of malignant PCs was in the spleen (SPL) 3 weeks after injection (D) and the survival of mice over time (E). Representative experiment out of 2 involving groups of n = 10 mice. (F and G) WT mice were injected with anti-CD226, anti-CD155, or control IgG (cIg) before Vk12653 MM cell injection. (F) Mean serum γ-globulin level ± SEM 3 weeks after MM injection. (G) Graphs showing the percentages of B220–CD138+ PCs in the SPL and BM. Representative experiment out of 2 involving groups of n = 10 mice. (H) Cd155–/–, Cd155+/–, and WT littermates were injected with anti-CD155 or control IgG before Vk*MYC challenge. Graph showing the number of B220–CD138+ PCs in the SPL. Data are from 2 pooled experiments involving groups of n = 7–14 mice. Each symbol represents 1 individual mouse. *P < 0.05, **P < 0.01, ***P < 0.001. Kruskall-Wallis test was used for multiple comparisons, Mann-Whitney U test was used for single comparison between groups, and Mantel-Cox test was used for survival analysis.