Monocyte chemoattractant protein 1 (MCP‐1/CCL2) contributes to thymus atrophy in acute myeloid leukemia

Abstract

Recent studies on acute myelogenous leukemia (AML) patients have revealed the existence of T-cell immunodeficiencies, characterized by peripheral T lymphocytes that are unable to interact with blasts, reduced thymic emigrants and oligoclonal restricted repertoires. These observations suggest that there is a profound thymic dysregulation, which is difficult to study in AML patients. Using the C1498 AML mouse model, we demonstrated that leukemia development was associated with thymus atrophy, which was defined by abnormal organ weight and reduced cellularity. In addition, we observed a dramatic loss of peripheral CD4 + and CD8 + T-cell numbers with increased frequencies of CD4 + FoxP3 + regulatory and activated/memory T cells. Investigating the mechanisms leading to this atrophy, we observed a significant accumulation of the monocyte chemoattractant protein 1 (MCP-1/CCL2) in thymi of leukemic mice. Treatment of AML-bearing animals with a blocking anti-CCL2 antibody revealed a lower tumor burden, augmented antileukemic T-cell responses, and improved survival rate compared to nontreated mice. These results were not observed when neutralization of CCL2 was performed in thymectomized mice. Altogether, we show that the CCL2 protein participates in thymic atrophy in AML mice, and this could have important implications for future immunotherapeutic strategies.Keywords: Acute myeloid leukemia r MCP-1/CCL2 r mouse model r T-cell response r thymus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAcute myeloid leukemia (AML) is characterized by impaired hematopoiesis. At the time of diagnosis and prior to chemotherapy, it has been shown that myeloid and plasmacytoid dendritic cell (DC) subsets are also affected by leukemogenesis and may exhibit the leukemic genotype. However, the myeloid-derived DCs retain their maturation capacity and ability to stimulate T lymphocytes [1]. Despite these observations, poor immune T-cell Correspondence: Dr. Carine Brinster e-mail: carine.brinster@inserm.fr responses are associated with AML in patients [2,3], and this immunodeficiency has been suggested to promote the expansion of malignant cells [4]. AML patients have normal-to-reduced levels of peripheral total CD3 + T lymphocytes that are unable to form effective immune synapses with autologous blasts [5]. Previous studies have described increased levels of circulating immunosuppressive CD4 + CD25 high regulatory T cells (Treg) in patients with untreated AML [6,7], which may contribute to the induction of tolerance to the leukemic cells. Furthermore, an altered T-cell repertoire associated with clonal expansion of certain T-cell receptor (TCR) Vβ subsets has been found in leukemic patients [8] Results Leukemia leads to thymic atrophyIn patients, the leukemic process appears to contribute to a profound state of immune suppression that affects the T-cell compartment [5]. Therefore, we investigated to what extent T-cell phenotype, function, and thymic differentiation ...

Acute Thymic Involution and Mechanisms for Recovery

“…MCP-1/CCL2 signaling is also associated with ATI in acute myelogenous leukemia (AML), where it is characterized by loss of peripheral DP thymocytes and increased expression of CD4 + Foxp3 + thymocytes in a mouse model. This investigation also found positive immunotherapeutic effects of anti-CCL2 antibody treatment in AML-bearing mice (Driss et al 2015).…”

Macrophages and myeloid derived suppressor cells-independent dysregulation of thymopoiesis by CCL2 in acute myeloid leukemia

“…We next examined whether MDSC or macrophages could be attracted to the thymus and suppress thymocytes activation, proliferation or favor their death. We found no thymic recruitment of CD11b + myeloid cells during AML but we described an up-regulation of the CCR2 expression on thymocytes (figure 1) [15] . A recent study indicates that thymic CCL2 expression increases upon inflammatory/infectious conditions and facilitates the entry of CCR2 + activated T cells [17] .…”

“…Interestingly, we showed that thymic CCL2 mRNA and proteins levels also increased during AML and that leukemic mice presented an accelerated thymic involution resulting in a peripheral T-cell lymphopenia [15] . As AML patients present variable circulating T cells numbers and reduced thymic emigrant T lymphocytes, we assessed the role of CCL2 in thymic function [16] .…”

“…Mice that received the leukemic cells presented increasing CCL2 protein rates in the sera during AML development [15] . Neutralizing CCL2 in vivo resulted in an enhanced mice survival, a lowered tumor burden, reduced organs invasion and an increased anti-leukemic T-cell response [15] . As observed in patients, we demonstrated that CCR2 was expressed by about 32% leukemic cells (unpublished data).…”

Tumor Arrests DN2 to DN3 Pro T Cell Transition and Promotes Its Conversion to Thymic Dendritic Cells by Reciprocally Regulating Notch1 and Ikaros Signaling

“…In GBM patients, a significant deficiency in the production of mature T cells is observed along with thymic involution (22). Recent studies on lymphoma patients also revealed the existence of T-cell dysfunction, with reduced output of thymic emigrants from atrophied thymus (23,24) suggesting that tumor cell-secreted factors might contribute to blocking intra-thymic T-cell development. In transplantable T-cell lymphoma, murine hosts show tumor growth-dependent immunosuppression, which is correlated well with a block in early T-cell development in atrophied thymus (25).…”