The immune system can identify and eliminate cancer cells through both innate and adaptive mechanisms; however, such antitumor responses can be inhibited by the microenvironment through a process known as immunosuppression. Cancer immunotherapy aims to manipulate both immunosuppressive and immunostimulatory mechanisms to increase the anticancer immune response. Therefore, it is important to understand tumor-infiltrating immune cells and their role in tumor growth and suppression. Tissue context is also important, as the interaction between malignant and immune cells plays a dynamic role in carcinogenesis, driven by a network of cytokines, chemokines, and growth factors. Reviewed below are the main immune system effector cells, their established cell-surface markers, and their function in cancer progression.
T cells are key actors of the adaptive immune system, are commonly identified by CD3 expression, and detect antigen through T cell receptors (TCRs), which recognize peptides presented by the major histocompatibility complex (MHC). Circulating tumor cell antigens are delivered to lymph nodes, where they are displayed to CD4+ and CD8+ T cells, also known as T helper and cytotoxic T cells, respectively. Following activation, T helper cells release a variety of cytokines, including IFNγ. Cytotoxic T cells recognize cells expressing tumor-specific antigens and kill them through perforin- or granzyme-induced apoptosis.
Expression of a variety of molecules is used to indicate T cell function. Both CD69 and CD25 are upregulated via TCR signaling but with distinctive kinetics, with CD69 detectable within hours of TCR ligation and CD25 increasing later. T cell exhaustion, defined by poor effector function and which arises during chronic infections and cancer, is characterized by expression of PD-1, TIM-3, and LAG3; however, these molecules are also upregulated during T cell activation. Other types of T cells – including naïve, memory, and effector – are distinguished from one another via a combination of CD45RA, CD45RO, and CD62L or CCR7. Multiple subtypes of CD4+ T cells that secrete different cytokines – and induce different immune responses – can be identified by unique expression of transcription factors. For example, T-Bet, typically expressed by Th1 cells, generally denotes an antitumor phenotype and IFNγ production. FoxP3, expressed by regulatory T cells (Treg), signifies a protumor phenotype that suppresses the antitumor immune response through cytokine production and other mechanisms.
Dendritic cells (DCs) are part of the innate immune system and play a key role in initiating adaptive immunity via both antigen presentation to activate naïve T cells and cytokine secretion. DCs are broadly divided into plasmacytoid and conventional subclasses. Plasmacytoid DCs are identified by co-expression of Siglec-H and CD317 and specialize in producing large amounts of type I IFNγ, whereas conventional DCs are characterized by co-expression of CD11c and HLA-DR and specialize in antigen presentation to T cells. Conventional DCs are further subdivided into those that express CD1c and facilitate activation of CD4+ T cells and those that express CD141, XCR1, or CLEC9A and activate CD8+ T cells by cross-presentation.
Macrophages are also cells of the innate immune system and are identified by expression of CD68 and MHCII and lack of CD11c. They specialize in phagocytosis and also secrete cytokines that influence the immune response. Macrophages generally are classified as pro-inflammatory (M1-like) or anti-inflammatory (M2-like). M1-like macrophages are identified by expression of CD80, CD86, or iNOS and promote the antitumor immune response by phagocytosis of malignant cells and production of T cell-activating ligands. Conversely, M2-like macrophages are identified by expression of CD163 or CD206 and can promote tumor growth through secretion of immunosuppressive cytokines, such as IL-10, and by promoting a Th2 response. M2 macrophages can also express the immunosuppressive enzyme arginase, which depletes arginine from the tumor microenvironment, leading to reduced T cell proliferation and function.
Natural killer (NK) cells represent the primary innate immune cell type. They recognize and kill cancer by detecting downregulation of MHC class I on tumor cells and/or by detecting upregulation of ligands on tumor cells that bind to activating receptors on NK cells. NK cells are commonly identified by a combination of CD56 and CD16 and lack of CD3 expression.
Finally, myeloid-derived suppressor cells (MDSCs) are a diverse population of immature immunosuppressive cells that are present in a variety of tumors. They have been shown to inhibit CD8+ T cell activation through the expression of NOS2 and arginase 1, induce Treg development, and polarize macrophages to an M2-like phenotype. MDSCs consist of 2 large groups of cells, termed monocytic or polymorphonuclear. Several open questions remain regarding these immunosuppressive cells, including whether they are truly distinct from neutrophils and monocytes, the mechanisms regulating their accumulation and differentiation, and how they contribute to resistance to anticancer therapies. The specific markers of MDSCs remain under active investigation. Currently, they are most often identified by expression of CD11b, lack of HLA-DR expression, and expression of either CD14 for monocytic MDSCs or CD15 for polymorphonuclear MDSCs.
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.