Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC)

Abstract

Granulocytic-Myeloid-derived suppressor cells (G-MDSC) are increased in Multiple Myeloma (MM) patients but the mechanisms of G-MDSC generation are still unknown. There are many evidences of the role of mesenchymal stem cells (MSC) in promoting MM cell growth, survival and drug-resistance. We here used a specific experimental model in vitro to evaluate the ability of MSC to induce G-MDSC. We found that although MSC derived from healthy donors (HD), MGUS and MM were able to generate the same amount of MDSC, only MM-MSC-educated G-MDSC exhibited suppressive ability. In addition, in comparison with MSC derived from HD, MM-MSC produce higher amount of immune-modulatory factors that could be involved in MDSC induction. Compared to G-MDSC obtained from co-culture models with MSC from healthy subjects, both MGUS and MM-MSC-educated G-MDSC showed increase of immune-modulatory factors. However, only MM-MSC educated G-MDSC 1) up-regulated immune-suppressive factors as ARG1 and TNFα, 2) expressed higher levels of PROK2, important in angiogenesis and inflammatory process, and 3) showed ability to digest bone matrix.Our data demonstrate that MM-MSC are functionally different from healthy subjects and MGUS-MSC, supporting an evolving concept regarding the contribution of MM-MSC to tumor development and progression.

Recent advances on the crosstalk between neutrophils and B or T lymphocytes

“…The existence of such a variety of immunosuppressive mechanisms might be related to the many different types of immunosuppressive neutrophil populations, conditioned by external factors. Cytokines such as IFN‐ γ and granulocyte–macrophage colony‐stimulating factor, or the direct contact with mesenchymal stem cells or tumour cells, have all been proposed to induce a suppressive phenotype in neutrophils from healthy donors. In this context, evidence that immunosuppressive neutrophil populations are present in the spleen, placenta, airways, or in tumours, already exists, but our understanding of the relationship between circulating and tissue neutrophils is still in its infancy.…”

Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

“…Multiple myeloma PMN-MDSCs are induced by multiple myeloma-related mesenchymal stem cells to have high expression of ARG1 and exert immunosuppressive function in tumor [103] Multiple myeloma PMN-MDSCs limit the anti-tumor response of T cells by increase the expression of ARG1 and other suppressive molecules, which is correlated with the expression of IL-18 [104] Head and neck cancer and urological cancers Overexpression of fatty acid transport protein 2 (FATP2) in PMN-MDSCs is conductive to tumor growth by the synthesis of PGE2 [29] Lymphomas are malignant tumors derived from the lymphatic hematopoietic system and are divided into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) [106]. Several studies have uncovered that in NHL, including B cell NHL, diffuse large B cell lymphoma and NK/T cell NHL, increased expression of ARG1, IDO and iNOS in MDSCs is relevant to the enhancement of tumor growth and suppression of T cells [107][108][109][110].…”

“…Multiple myeloma PMN-MDSCs are induced by multiple myeloma-related mesenchymal stem cells to have high expression of ARG1 and exert immunosuppressive function in tumor[103] …”

Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

“…Авторы проводили совместное культивирование мезенхимных стволовых клеток (МСК) из костного мозга пациентов (МГНЗ и ММ) или здоровых лиц с МПК здоровых доноров, чтобы генерировать г-MC из МПК. Выявлено, что МСК, полученные от здоровых доноров, пациентов с МГНЗ или ММ, были способны генерировать одинаковое количество MC, но только образованные от ММ-МСК MC имели супрессивные способности [61].…”