Granulocyte-derived Resistin Inhibits Monocyte Maturation and Promotes an Immunosuppressive Phenotype in Chronic Myelomonocytic Leukemia Monocytes

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Abstract

Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by expansion of malignant monocytes. However, as a stem cell neoplasm, the disease clone comprises most blood lineages, including granulocytes. To investigate their pathogenic contribution, we performed extensive phenotypic, transcriptomic and functional characterization of CMML granulocytes. These cells exhibited reduced granularity and impaired maturation, the latter of which is associated with poor prognosis. Functionally, CMML granulocytes displayed reduced phagocytic capacity and impaired NETosis, together with aberrant gene expression programs. Notably, RETN, encoding the chemokine resistin, was uniquely upregulated in CMML granulocytes. Accordingly, resistin levels were 10-fold higher in CMML plasma, correlating with inferior survival. Ex vivo exposure to resistin directly blocked monocyte maturation and macrophage differentiation, partly via TLR4 interaction, recapitulating the classical monocytosis repartitioning phenotype that characterizes CMML. Resistin-treated monocytes upregulated gene signatures related to immune suppression and myeloid-derived suppressor cell phenotype. Consistent with these findings, CMML patients displayed higher Treg proportions and Th2/Th1 ratios. Furthermore, we demonstrated that resistin directly skews the Th2/Th1 ratio via binding to monocytes. Thus, CMML granulocytes produce high levels of resistin, which contributes to defective monocyte maturation and induction of myeloid-derived suppressor cell features in monocytes, thereby fostering an immune-suppressive state in this disease.

Authors

Nathan J. Hull, Rachel Cant, Laura A. Guest, Yu-Hung Wang, Kristian Gurashi, Roberto Paredes, Carlos Rivera Rivera, Revekka Lefkati, Hector Huerga Encabo, Chien-Chin Lin, Hwei-Fang Tien, Robert Sellers, Sudhakar Sahoo, Dominique Bonnet, Eric Solary, Dorothee Selimoglu-Buet, Daniel H. Wiseman, Kiran Batta