Spontaneous onset and transplant models of the Vk*MYC mouse show immunological sequelae comparable to human multiple myeloma

Abstract

BackgroundThe Vk*MYC transgenic and transplant mouse models of multiple myeloma (MM) are well established as a research tool for anti-myeloma drug discovery. However, little is known of the immune response in these models. Understanding the immunological relevance of these models is of increasing importance as immunotherapeutic drugs are developed against MM.MethodsWe set out to examine how cellular immunity is affected in Vk*MYC mouse models and compare that to the immunology of patients with newly diagnosed and relapsed/refractory MM.ResultsWe found that there were significant immunological responses in mice developing either spontaneous (transgenic) or transplanted MM as a consequence of the degree of tumor burden. Particularly striking were the profound B cell lymphopenia and the expansion of CD8+ effector memory T cells within the lymphocyte population that progressively developed with advancing disease burden, mirroring changes seen in human MM. High disease burden was also associated with increased inflammatory cytokine production by T lymphocytes, which is more fitting with relapsed/refractory MM in humans.ConclusionsThese findings have important implications for the application of this mouse model in the development of MM immunotherapies.Trial registration LitVacc ANZCTR trial ID ACTRN12613000344796; RevLite ANZCTR trial ID NCT00482261

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

“…Thus, in MM cells, AHR functions as an important transcriptional activator of the polyamine biosynthetic pathway, whereas CLF antagonizes this activation. in which c-MYC expression is sporadically activated in B cells, causing the spontaneous development of MM with dynamics and features that closely recapitulate those observed in human MM patients (88,92). Of note, among more than 30 drugs that have been evaluated in clinical trials for MM, 73% of those that induced a response in the Vk*MYC model have been approved for use in the treatment of patients (87,93) In a pilot experiment, mice with similar disease burdens (as measured by serum IgG secretion levels; see Figure 6A, week 0) were randomized into 1 of 2 groups and treated with either vehicle in PBS or CLF, as described above.…”

“…Vk*MYC mice are an immunocompetent model of spontaneously arising myeloma, in which the actual bone marrow microenvironment is involved in the sustainment of the malignancy, similar to what naturally occurs in the human disease (88,92). Thus, impairment of AHR signaling, as caused by CLF treatment, may result in both intrinsic and extrinsic effects: inhibition of polyamine biosynthesis and disruption of MM-bone marrow microenvironment interactions, respectively.…”

Bone marrow transplantation generates T cell–dependent control of myeloma in mice

“…For subsequent experiments, myeloma cell clones were propagated in house in B6.WT and RAGγc -/mice, respectively. Transplantable VK12653 and Vk12598 myeloma cell clones have been shown to have immunological outcomes similar to those of spontaneous-onset myeloma in Vk*MYC-transgenic mice (70). Recipient mice (hereafter referred to as MM-bearing mice) were injected i.v.…”

Impact of age-, cancer-, and treatment-driven inflammation on T cell function and immunotherapy

“…There are also clear shifts more generally in T cell phenotypes in MM patients, with a decrease in T N cells and an increase in T EM cells and T EMRA cells 104,105 ( Figure 2 ). In CD8 T cells, the decrease in T N cells is seen at initial diagnosis but, in CD4 T cells, T N cells are relatively preserved at initial diagnosis but are noted to be markedly reduced by relapsed/refractory disease.…”

“…In CD8 T cells, the decrease in T N cells is seen at initial diagnosis but, in CD4 T cells, T N cells are relatively preserved at initial diagnosis but are noted to be markedly reduced by relapsed/refractory disease. As a result, a decrease in the CD4:8 ratio is a characteristic marker of disease progression in MM 104,105 . An analogous shift, with an early loss of CD8 T N cells followed by a loss of CD4 T N cells, is seen during normal immune aging.…”