The overall structure of the murine immune system is comparable to that of humans, consisting of both innate and adaptive components, and its efficacy is regulated in cancer. Importantly, mouse models have contributed substantially to our understanding of cancer biology, including the validation of cancer genes, the discovery of tumor biomarkers, and the assessment of investigational therapeutics. As in humans, mouse immune cells modulate tumor growth and suppression, driven by a complex network of cytokines, chemokines, and growth factors. Described below are the various populations of murine immune cells.
Mouse T cells are characterized by CD3 expression and are subdivided into CD4+ helper and CD8+ cytotoxic groups. T cell activation increases expression of CD69 and CD25, which are frequently used as markers of activation. CD8+ cytotoxic cells release serine proteases (granzyme) and pore-forming cytolytic proteins (perforin) to lyse target cancer cells, while CD4+ helper cells coordinate the immune response through secretion of various cytokines. As in humans, exhausted murine T cells express some combination of PD-1, TIM-3, and LAG-3; although, these molecules can also be expressed upon T cell activation. Naïve, memory, and effector T cells in mice can be distinguished through expression of CD62L, IL7Ra, and CD44. Multiple cytokine-producing subsets of CD4+ cells are characterized by expression of transcription factors, such as T-bet for antitumor Th1 cells and FoxP3/CD25 for protumor Treg.
Murine dendritic cells (DCs) present antigen to CD4+ and CD8+ T cells. Like human DCs, mouse cells are divided into plasmacytoid and conventional subclasses. Plasmacytoid DCs co-express Siglec-H and CD317 and produce type I IFNγ, while conventional DCs are characterized by expression of CD11c and MHCII. DCs that excel in cross-presentation to CD8+ T cells can be identified by expression of XCR1 or CLEC9A.
In mice, as in humans, apoptotic tumor cells can be discarded by macrophages, which express an adhesion G-protein-coupled receptor known as F4/80. Murine macrophage polarization also occurs, with M1-like cells identified by expression of CD86, CD80, or iNOS and M2-like cells identified by expression of CD163, CD206, or arginase. Expression of functional iNOS and its mRNA induction by IFNγ have been well-established in mice.
Natural killer (NK) cells of the murine innate immune system recognize and kill cancer cells via a combination of activating and inhibitory receptors that allows NK cells to kill cancer cells without harming the host. They can be identified by expression of NKG2D, NK1.1, or NKp46 in combination with a lack of CD3 expression. NK cells also produce immunoregulatory cytokines. Murine NK cell homeostasis and development have strongly been attributed to the SH-2-containing phosphatase SHIP1.
Lastly, murine myeloid-derived suppressor cells (MDSCs) express high levels of CD11b, arginase, and the granulocytic marker GR1, which is itself composed of the membrane proteins Ly6C and Ly6G. In mice, MDSCs have been found in tumors as well as in bone marrow, blood, spleen, liver, and lung. They are broadly categorized into monocytic (CD11b+ Ly6G- Ly6Chi) and polymophonuclear (CD11b+ Ly6G+ Ly6Clo) groups, the latter being the predominant population in most cancers. However, distinguishing peripheral mononuclear cells from neutrophils remains challenging and is an area of ongoing investigation.
We would like to thank Kate Fitzgerald, Ph.D., UMass Medical School, Courtney Betts, Ph.D. Oregon Health and Science University, and Shadmehr (Shawn) Demehri, M.D., Ph.D.Massachusetts General Hospital Cancer Center, Harvard Medical School for reviewing this diagram.