Tumor‐associated macrophages regulate the function of cytotoxic T lymphocyte through <scp>PD</scp>‐1/<scp>PD‐L1</scp> pathway in multiple myeloma

Zhang, Jiangbo; Liu, Zhaoyun; Cao, Panpan; Wang, Hao; Liu, Hui; Hua, Luoming; Xue, Hua; Fu, Rong

doi:10.1002/cam4.4814

Cited by 9 publications

(6 citation statements)

References 38 publications

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“…In vivo, the administration of the anti CSF-1 receptor antibody CS7 significantly reduced the MM tumor burden, while the in vitro administration of low-dose CS7 could contribute to TAM polarization towards an M1 subtype [110]. M1 TAM showed an improved antigen-presenting capacity and the ability to enhance a cytotoxic CD4 + T cell response, further supporting the hypothesis that M2 TAM, conversely, play a relevant role in the decreased T cell activation and resulting immunosuppression reported in MM, ultimately leading to disease progression [110].…”

Section: Mouse Model Studiesmentioning

confidence: 99%

“…In vitro, an anti-CD47 antibody significantly improved the ability of macrophage to engulf MM cells [113,114]. In addition, TAM could drive immune tolerance, due to co-culture with TAM could increase programmed death receptor 1(PD1) expression on CD8 + T cells and programmed death receptor ligand 1 (PD-L1) expression on MM cells [102,110].…”

Section: Human Studiesmentioning

confidence: 99%

“…Immune checkpoints represent inhibitory mechanisms frequently used by tumor cells to escape from recognition and killing by cells of the host immune system. Anti PD-1/PD-L1 monoclonal antibodies demonstrated high efficacy in HL treatment, but treatment results were disappointing in MM [110,144]. The PD-L1/PD-1 axis was investigated by flow cytometry in the BM samples of 141 patients, including MGUS, smoldering MM (SMM) and active MM, either newly diagnosed or R/R cases.…”

Section: Restoration Of T-cell Response and Inhibition Of Cd47/sirpα ...mentioning

confidence: 99%

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Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications

et al. 2023

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Multiple myeloma (MM) is characterized by multiple relapse and, despite the introduction of novel therapies, the disease becomes ultimately drug-resistant. The tumor microenvironment (TME) within the bone marrow niche includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages, with a complex cross-talk between these cells and the MM tumor cells. Tumor-associated macrophages (TAM) have an important role in the MM pathogenesis, since they could promote plasma cells proliferation and angiogenesis, further supporting MM immune evasion and progression. TAM are polarized towards M1 (classically activated, antitumor activity) and M2 (alternatively activated, pro-tumor activity) subtypes. Many studies demonstrated a correlation between TAM, disease progression, drug-resistance and reduced survival in lymphoproliferative neoplasms, including MM. MM plasma cells in vitro could favor an M2 TAM polarization. Moreover, a possible correlation between the pro-tumor effect of M2 TAM and a reduced sensitivity to proteasome inhibitors and immunomodulatory drugs was hypothesized. Several clinical studies confirmed CD68/CD163 double-positive M2 TAM were associated with increased microvessel density, chemoresistance and reduced survival, independently of the MM stage. This review provided an overview of the biology and clinical relevance of TAM in MM, as well as a comprehensive evaluation of a potential TAM-targeted immunotherapy.

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Section: Mouse Model Studiesmentioning

confidence: 99%

Section: Human Studiesmentioning

confidence: 99%

Section: Restoration Of T-cell Response and Inhibition Of Cd47/sirpα ...mentioning

confidence: 99%

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Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications

et al. 2023

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“…IL-32γ can promote drug resistance in MM through macrophages and modify macrophages towards an M2 phenotype [316]. Increased TAMs in MM patients can stop the functions of cytotoxic T lymphocytes (through the PD-1/PD-L1 pathway) and contribute to the evasion of the immune system by myeloma cells [317]. Exosomes, derived from MM containing IL-32γ, can increase the expression of PD-L1 by macrophages and lead to immune evasion.…”

Section: Macrophage Role In Multiple Myelomamentioning

confidence: 99%

Macrophage-Based Therapeutic Strategies in Hematologic Malignancies

Khalili,

Zeinali,

Moghadam Fard

et al. 2023

Cancers

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Macrophages are types of immune cells, with ambivalent functions in tumor growth, which depend on the specific environment in which they reside. Tumor-associated macrophages (TAMs) are a diverse population of immunosuppressive myeloid cells that play significant roles in several malignancies. TAM infiltration in malignancies has been linked to a poor prognosis and limited response to treatments, including those using checkpoint inhibitors. Understanding the precise mechanisms through which macrophages contribute to tumor growth is an active area of research as targeting these cells may offer potential therapeutic approaches for cancer treatment. Numerous investigations have focused on anti-TAM-based methods that try to eliminate, rewire, or target the functional mediators released by these cells. Considering the importance of these strategies in the reversion of tumor resistance to conventional therapies and immune modulatory vaccination could be an appealing approach for the immunosuppressive targeting of myeloid cells in the tumor microenvironment (TME). The combination of reprogramming and TAM depletion is a special feature of this approach compared to other clinical strategies. Thus, the present review aims to comprehensively overview the pleiotropic activities of TAMs and their involvement in various stages of cancer development as a potent drug target, with a focus on hematologic tumors.

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“…Recent research suggests that macrophages contribute to the growth, viability, and drug resistance of myeloma cells through both direct and indirect mechanisms 17,18 . Moreover, studies have demonstrated an expansion of TAMs in patients with MM and their involvement in suppressing the anti‐tumor activity of cytotoxic T lymphocytes (CTLs) via the PD‐1/PD‐L1 signaling pathway, thus aiding in the immune evasion of myeloma cells 19 . Despite these findings, the precise mechanisms underlying the immunosuppressive polarization of TAMs in MM remain incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

miR‐34a promotes the immunosuppressive function of multiple myeloma‐associated macrophages by dampening the TLR‐9 signaling

Zhang,

Luo

et al. 2024

Cancer Medicine

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BackgroundPromising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR‐T) cell therapy. However, a portion of MM patients do not respond to CAR‐T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR‐34a on the immunosuppressive polarization of macrophages obtained from MM patients.MethodsThe levels of miR‐34a and TLR9 (Toll‐like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co‐culture experiments were conducted to evaluate the immunomodulatory impact of MM‐associated macrophages on CAR‐T cells.ResultsThere was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR‐34a in MM‐associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co‐culture system and an animal model, MM‐associated macrophages suppressed the activity and tumoricidal effect of CAR‐T cells in a miR‐34a‐dependent manner.ConclusionThe findings imply that targeting the macrophage miR‐34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR‐T therapy in MM patients.

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Tumor‐associated macrophages regulate the function of cytotoxic T lymphocyte through PD‐1/PD‐L1 pathway in multiple myeloma

Cited by 9 publications

References 38 publications

Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications

Tumor-Associated Macrophages in Multiple Myeloma: Key Role in Disease Biology and Potential Therapeutic Implications

Macrophage-Based Therapeutic Strategies in Hematologic Malignancies

miR‐34a promotes the immunosuppressive function of multiple myeloma‐associated macrophages by dampening the TLR‐9 signaling

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