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

Abstract

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.

'Trained immunity: consequences for lymphoid malignancies

“…An increased tolerogenic state of monocytes and macrophages has clearly been implicated in lymphoid malignancies. 82 Nevertheless, whether vaccination with BCG or β-glucan can restore the balance and skew tumor associated macrophages from the M2 towards a more M1 phenotype with beneficial anti-tumor characteristics, Trained immunity in hematology haematologica | 2016; 101 (12) 1465 remains to be proven. However, recently data have shown that another type of immunosuppressive myeloid cell, i.e., MDSC, can be successfully reprogrammed by exposure to β-glucan, resulting in the loss of its immunosuppressive phenotype and gain of enhanced antigen presenting capacities.…”

Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

“…60 Studies in CLL, for example, suggest that monocyte-derived suppressor cells with high PD-L1 expression and/ or skewed monocyte subpopulations are increased in patients and preclinical models and modulate T-cell responses. 76,77 In multiple solid cancer types, clinical responses were observed in patients with high PD-L1 expression on tumor-infiltrating immune cells and in those with TH1 gene signatures and Tcell CTLA-4 expression at baseline. 23 Immune dysfunction might also be mediated by other (potentially inducible) immune checkpoint receptor-ligand interactions, for example, by the binding of PD-1 to PD-L2 78 or by signaling via CD200, CD270 and CD276, 27 or by additional tumor-associated and/ or genetic determinants.…”

BRAFV600E accelerates disease progression and enhances immune suppression in a mouse model of B-cell leukemia

“…41 The impact of the BRAF VE mutation on the myeloid compartment was therefore evaluated, again using the adoptive transfer model. Mice were engrafted with either BRAF WT or BRAF VE leukemia cells, and upon achieving disease, spleens were evaluated by flow cytometry.…”

“…Alterations in monocytic subsets were also observed, with a shift from a patrolling to an MDSC immunophenotype in contrast to what has been reported in Em-TCL1 mice. 41 Depletion of myeloid cells, including patrolling monocytes in the Em-TCL1 adoptive transfer model, controls CLL-like disease development, 41 but the patrolling monocytes also have antitumor function for suppressing tumor metastasis to lung by increasing natural killer cell-mediated killing of metastatic tumor cells in multiple metastatic mouse models. 54 Although the function of patrolling cells in the cancer context is controversial, the observation of the affected myeloid cells in our mouse model indicates that BRAF V600E leukemia cells can skew these cells to an immune suppressive phenotype.…”