Monocyte chemoattractant protein 1 (MCP-1/CCL2) contributes to thymus atrophy in acute myeloid leukemia.
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.
Institut pour la Recherche sur le Cancer de Lille (IRCL), INSERM U.837, Lille Cedex, France.
Virginie
V
Driss
Bruno
B
Quesnel
Carine
C
Brinster
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001284:Atrophy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D009929:Organ Size; D016019:Survival Analysis; D013934:Thymectomy; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
D057134:Antibodies, Neutralizing; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
Acute myeloid leukemia; MCP-1/CCL2; T-cell response; mouse model; thymus