IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression

In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell-derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)-deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.

Tumor-derived exosomes modulate PD-L1 expression in monocytes.

Nanomedicines for the treatment of hematological malignancies

// Stefania Fiorcari 1, * , Rossana Maffei 1, * , Valentina Audrito 2 , Silvia Martinelli 1 , Elisa ten Hacken 3 , Patrizia Zucchini 1 , Giulia Grisendi 1 , Leonardo Potenza 1 , Mario Luppi 1 , Jan A. Burger 3 , Silvia Deaglio 2 , Roberto Marasca 1 1 Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy 2 Department of Medical Sciences, University of Turin and Human Genetics Foundation, Turin, Italy 3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Roberto Marasca, email: roberto.marasca@unimore.it Stefania Fiorcari, email: stefania.fiorcari@unimore.it Keywords: CLL, ibrutinib, microenvironment, nurse-like cells, immune modulation Received: June 08, 2016     Accepted: August 15, 2016     Published: September 01, 2016 ABSTRACT In lymphoid organs, nurse-like cells (NLCs) show properties of tumor-associated macrophages, playing a crucial role in chronic lymphocytic leukemia (CLL) cell survival. Ibrutinib, a potent inhibitor of Bruton’s tyrosine kinase (BTK), is able to counteract pro-survival signals in CLL cells. Since the effects on CLL cells have been studied in the last years, less is known about the influence of ibrutinib on NLCs properties. We sought to determine how ibrutinib modifies NLCs functions focusing on the balance between immunosuppressive and inflammatory features. Our data show that ibrutinib targets BTK expressed by NLCs modifying their phenotype and function. Treatment with ibrutinib reduces the phagocytic ability and increases the immunosuppressive profile of NLCs exacerbating the expression of M2 markers. Accordingly, ibrutinib hampers LPS-mediated signaling, decreasing STAT1 phosphorylation, while allows IL-4-mediated STAT6 phosphorylation. In addition, NLCs treated with ibrutinib are able to protect CLL cells from drug-induced apoptosis partially through the secretion of IL-10. Results from patient samples obtained prior and after 1 month of treatment with ibrutinib show an accentuation of CD206, CD11b and Tie2 in the monocytic population in the peripheral blood. Our study provides new insights into the immunomodulatory action of ibrutinib on monocyte/macrophage population in CLL.

Ibrutinib modifies the function of monocyte/macrophage population in chronic lymphocytic leukemia.

Despite progress in exploiting therapeutically the genetic vulnerabilities of leukemia and lymphoma, the outcome is often extended progression-free survival but not tumor eradication. Lymphomagenesis is not a tumor-autonomous process, and the onset and progression of tumors requires reciprocal crosstalk with the tumor microenvironment (TME). Minimal residual disease and immunosurveillance are also regulated by factors in the TME. Here, we dissect the stromal compartment in lymphoid organs, focusing on conditions that are prevalent in an autochthonous environment for lymphoid neoplasia. Identification of tumor-promoting factors is instrumental in the selection of therapeutic targets that are part of the immune system. Targeting the TME is an appealing treatment option for lymphoma because this compartment is subject to low selective pressure for mutations.

Targeting the Tumor Microenvironment of Leukemia and Lymphoma.

Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the Eμ-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-II(hi) dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-α and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.

Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.

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Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo.