Figure 2.

Immune landscape in early and late tumors. (A) Early tumors consist of non-aggressive hemopoietic cells such as classical monocytes, M0 macrophages, M1 pro-inflammatory/anti-tumor macrophages, NK1 and NK2 natural killer cell subtypes, conventional dendritic cells, naïve T cells, Follicular B cells. (B) As the tumor progresses to advanced stages, multiple immune cells converge to support pro-tumorigenic/anti-tumorigenic functions. Tumor-derived factors such as TGF-b, FGF or PDGF, interleukins, etc. are responsible for the diversification of immune cell types during cancer development. Moreover, with an increase in hypoxic and inflammatory core sites and activation of angiogenic switches, immune cells alter their conventional anti-tumorigenic behavior to pro-tumorigenic potential. (C) Monocyte subtypes, especially classical CD14+, Non-classical CD16+, TIE2+ cells, and intermediate cells, are present in late tumors. Hypoxia is a well-defined factor that leads to the regulation and infiltration of these monocytes into TME. (D) Types of macrophages present in late tumors: M2 (pro-tumorigenic) is the massively distributed subtype in late tumors and is related to poor prognosis and patient survival. They secrete a plethora of pro-tumorigenic proteases, cytokines and growth factors (for example, VEGF, EGF, which participates in a paracrine signaling loop through tumor-secreted CSF-1). The number of M1 macrophages are less in late tumors but comparatively higher in early tumors as they are anti-tumorigenic. MDSCs (myeloid-derived suppressor cells) are the recently discovered heterogeneous group of immune cells that are immunosuppressive. (E) Types of different neutrophils present in late tumors: majorly 5 types of neutrophils are known which are evolutionarily categorized from two subsets i.e., pro-tumorigenic and anti-tumorigenic. (F) Subtypes of T cells that play a role in shaping tumor immunity: helper, cytotoxic and effector memory T cells fight against growing tumors directly or indirectly by antigen presentation, cytotoxic granzyme and perforin release, cytotoxic T cells upon exhaustion are termed as exhaustive T cells and are signature of aggressive tumors, regulatory T cells are immunosuppressive, therefore linked with poor patient survival, gdT cells are a significant focus of cancer immunotherapy as they have strong cytokine production ability. (G) Types of B cells found in late-stage tumors, their antibody-secreting skills are linked with prolonged patient survival. But regulatory B cells are immunosuppressive. (H) Natural killer (NK) cells shaping tumor immunity: these are the cytotoxic cells and express a specialized class of natural cytotoxicity receptors (NCRs) such as NKp30, NKp44, and NKp46 which initiate tumor targeting by recognition of heparan sulphate on cancer cells. (I) Different types of dendritic cells (DCs) present in late-stage tumors: these are the active cells and express co-stimulatory molecules having efficient anti-tumor immune responses.