TIGIT blockade repolarizes AML-associated TIGIT⁺M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis

Abstract

BackgroundLeukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).MethodsThe phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro.ResultsIn pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT+M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells.ConclusionOur findings suggest that immunosuppressive TIGIT+M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future.

A multidimensional analysis reveals distinct immune phenotypes and tertiary lymphoid structure-like aggregates in the bone marrow of pediatric acute myeloid leukemia

“…Therefore, repolarizing M2-like macrophages towards an M1-like phenotype could be a suitable immunotherapeutic option in pediatric AML patients with an immune-depleted BM (Duan & Luo, 2021; Li et al, 2022). Of interest, a recent study indicated that M2-like macrophages in the BM of adult AML patients showed increased expression of the immune checkpoints TIGIT and LAG-3 compared to healthy donors, and that TIGIT blockade was able to repolarize these M2-like macrophages to an M1-like phenotype (Brauneck et al, 2022). Thus, TIGIT and LAG-3 blockade may have beneficial effects on both the T cell and macrophage compartment, which encourages further evaluation of these agents in the preclinical setting.…”

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE

“…9,14,15 A mounting body of evidence underscores the extension of TIGIT expression to various innate immune cells, encompassing T cells, innate lymphoid cells, invariant natural killer T cells, and macrophages, instigating heightened immunosuppressive responses. [16][17][18] This revelation bears substantial implications for comprehending the regulatory role of TIGIT in immune function, transcending its established functions in T and NK cells.…”

The generation, activation, and polarization of monocyte-derived macrophages in human malignancies

“…In Acute Myeloid Leukemia (AML), cancer cells induce the differentiation and polarization of monocytes into LAMs via Gfi1, a transcription factor involved in macrophage development ( 130 ). Moreover, it was established that LAMs are associated with an unfavorable prognosis in AML patients ( 131 ). In T-ALL and chronic lymphocytic leukemia (CLL), the generation of LAMs is dependent on M-CSF.…”