Hi, everyone! I am Xiao Q~
The tumor microenvironment is a battlefield filled with smoke, where various immune cells are the main characters. Although different immune cells look different and exhibit their own abilities, they all share a common ancestor: hematopoietic stem cells (HSC).
In a healthy body, HSCs differentiate through four stages into different immune cells:
In the first stage, HSCs differentiate into multipotent progenitor cells (MPP);
In the second stage, MPP further differentiates into common lymphoid progenitor (CLP), common myelolymphoid progenitor (CMLP), and common myeloid progenitor (CMP);
In the third stage, CMP differentiates into granulocyte and macrophage progenitor (GMP), macrophage and dendritic cell progenitor (MDP), mast cell progenitor (MCP), megakaryocyte and erythroid progenitor (MEP), while CLP differentiates into common DC progenitor (CDP);
In the fourth stage, a series of immature myeloid cells (IMC) produced in the previous three stages migrate to different peripheral organs and mature into lymphocytes, granulocytes, dendritic cells, macrophages, mast cells, erythrocytes, and megakaryocytes, thereby performing various physiological functions[1].
Figure 1: The origin of MDSC: immature myeloid cells
However, in tumor patients, the story of hematopoietic stem cells (HSCs) is not as long and smooth.
Tumor cells secrete cytokines and chemokines that disrupt the differentiation process of HSCs, inhibiting the gradual differentiation of HSCs on one hand and inducing the continuous proliferation of immature myeloid cells on the other, resulting in a large number of abnormal immature myeloid cells collectively known as myeloid-derived suppressor cells (MDSC)[1].
Professor Dmitry I. Gabrilovich is an authority in the field of MDSC research, and in 2009 he proposed the definition of MDSC: MDSC is a group of immature cells derived from the bone marrow that are activated and mobilized under pathological conditions such as tumors and possess T cell suppressive functions[2].
As we know, flow cytometry is a powerful tool for identifying different immune cells; however, it appears quite powerless in the face of MDSC.
This is because MDSCs exhibit significant heterogeneity. One MDSC cell may have a completely different appearance and identity from another MDSC cell.
Due to the heterogeneous nature of MDSC, identifying MDSC has become a key challenge in the field of MDSC research.
Today, Xiao Q will peel back the layers of mystery surrounding MDSC~
After 40 years of research, scientists have reluctantly unified the molecular markers of MDSC; mice and humans have their own identification standards for MDSC.
MDSC is morphologically divided into monocytic MDSC (M-MDSC) resembling monocytes and granulocytic MDSC (G-MDSC) resembling granulocytes, which are two subgroups[3].
|
Species |
MDSC |
M-MDSC |
G-MDSC |
|
Mice |
Gr1+CD11b+ |
CD11b+Ly6G–Ly6Chi |
CD11b+Ly6G+Ly6Clow |
|
Humans |
– |
HLA-DR–CD11b+CD33+CD14+ |
HLA-DR–CD11b+CD33+CD15+ |
MDSC is essentially immature myeloid cells. Can we distinguish MDSC from immature myeloid cells (IMC) using the above MDSC markers?
No. Mice’s MDSC is certainly Gr1+CD11b+ cells, but Gr1+CD11b+ cells are not necessarily MDSC in mice.
From the perspective of cell surface molecular markers, MDSC and immature myeloid cells cannot be distinguished.
Scientists have used the cell surface markers of MDSC to detect the distribution of MDSC in key immune organs of humans and mice.
Since MDSC is activated and mobilized under pathological conditions such as tumors, the detection of MDSC surface protein markers in healthy humans or mice does not indicate the presence of MDSC; they can only be considered immature myeloid cells (IMC).
Figure 2: MDSC distribution: abundant in tumor patients
Specifically, under physiological conditions, human peripheral blood mononuclear cells contain only 0.5% IMC; in mice, the IMC content in the bone marrow is 20%-30%, and in the spleen, it is 2%-4%.
In contrast, in tumor patients, the MDSC in human PBMC and tumor tissues can increase up to 10 times; in mice, MDSC has been detected in peripheral blood, bone marrow, lymph nodes, spleen, lungs, liver, and tumors, especially in the spleen, where it can reach 20%-40%[2, 4].
Cell surface molecular markers are the first step in identifying MDSC; however, the phenotype cannot distinguish immature myeloid cells (IMC) from MDSC, nor can it differentiate PMN-MDSC from neutrophils or M-MDSC from monocytes.
Therefore, further functional and biochemical characteristics are needed to define MDSC. The function of MDSC is the second major element for identifying MDSC.
The main function of MDSC is to promote tumor development[5]. On one hand, MDSC supports tumor angiogenesis and promotes tumor invasion and metastasis;
On the other hand, MDSC actively suppresses the body’s immune response, including inhibiting the functions of CD8+ T cells, CD4+ T cells, NK cells, and B cells, promoting the conversion of CD4+ T cells to Treg (regulatory cells). MDSC can also transform into tumor-associated macrophages (TAM).
The key characteristic that distinguishes MDSC from immature myeloid cells (IMC) is that MDSC possesses immunosuppressive functions. Among these, the inhibition of CD8+ T cells is the “gold standard” for identifying MDSC[3].
The classic system for evaluating the immunosuppressive function of MDSC is the co-culture experiment of MDSC and CD8+ T cells, which can be divided into two main categories:
The first category is the antigen-specific system, which evaluates whether MDSC suppresses antigen-specific CD8+ T cells, using homologous peptides or allogeneic mixed lymphocyte reactions (MLR) to activate antigen-specific CD8+ T cells;
The second category evaluates whether MDSC suppresses non-antigen-specific CD8+ T cells, using CD3/CD28 or lectin to activate CD8+ T cells, and then adding purified MDSC.
In both co-culture systems, the “titration” of MDSC content is crucial, meaning that the number of CD8+ T cells is fixed while the amount of MDSC is gradually increased to observe whether the inhibition of CD8+ T cell proliferation and effector functions by MDSC gradually strengthens.
If experimental conditions permit, antigen-specific suppression experiments are more meaningful because they better simulate in vivo conditions.
Alright, that’s all for today. If you want to learn more about the regulatory mechanisms related to MDSC, understand the targeting strategies for MDSC, or follow Xiao Q to unlock detailed research methods on MDSC, be sure to follow me~
[References]
[1] D.I. Gabrilovich, S. Ostrand-Rosenberg, V. Bronte, Coordinated regulation of myeloid cells by tumours, Nat Rev Immunol 12(4) (2012) 253-68.
[2] D.I. Gabrilovich, S. Nagaraj, Myeloid-derived suppressor cells as regulators of the immune system, Nat Rev Immunol 9(3) (2009) 162-74.
[3] V. Bronte, S. Brandau, S.H. Chen, M.P. Colombo, A.B. Frey, T.F. Greten, S. Mandruzzato, P.J. Murray, A. Ochoa, S. Ostrand-Rosenberg, P.C. Rodriguez, A. Sica, V. Umansky, R.H. Vonderheide, D.I. Gabrilovich, Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards, Nat Commun 7 (2016) 12150.
[4] D.I. Gabrilovich, Myeloid-Derived Suppressor Cells, Cancer immunology research 5(1) (2017) 3-8.
[5] D. Marvel, D.I. Gabrilovich, Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected, J Clin Invest 125(9) (2015) 3356-64.
