Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers

Abstract

Our body is constantly exposed to pathogens or external threats, but with the immune response that our body can develop, we can fight off and defeat possible attacks or infections. Nevertheless, sometimes this threat comes from an internal factor. Situations such as the existence of a tumour also cause our immune system (IS) to be put on alert. Indeed, the link between immunology and cancer is evident these days, with IS being used as one of the important targets for treating cancer. Our IS is able to eliminate those abnormal or damaged cells found in our body, preventing the uncontrolled proliferation of tumour cells that can lead to cancer. However, in several cases, tumour cells can escape from the IS. It has been observed that immune cells, the extracellular matrix, blood vessels, fat cells and various molecules could support tumour growth and development. Thus, the developing tumour receives structural support, irrigation and energy, among other resources, making its survival and progression possible. All these components that accompany and help the tumour to survive and to grow are called the tumour microenvironment (TME). Given the importance of its presence in the tumour development process, this review will focus on one of the components of the TME: immune cells. Immune cells can support anti-tumour immune response protecting us against tumour cells; nevertheless, they can also behave as pro-tumoural cells, thus promoting tumour progression and survival. In this review, the anti-tumour and pro-tumour immunity of several immune cells will be discussed. In addition, the TME influence on this dual effect will be also analysed.

Keywords: cancer; immune cells; immune evasion; immune system; immunosurveillance; tumour microenvironment.

Figure 1

Hematopoiesis. The hematopoiesis process begins with the division of the hematopoietic stem cell (HSC), found in the bone marrow. This type of cell has the ability to be multipotent and self-renewing. HSCs, through the production of multipotent hematopoietic progenitor cells (HPCs) can give rise to two types of blood cell lines (myeloid and lymphoid lineage). Each of them, at the end of the process, will give rise to late precursors and mature cells forms through committed precursors. Mature cells are divided into three groups: red blood cells, platelets and leukocytes. Leukocytes form the innate and adaptive immunity, this latter subdivided in humoral (governed by B cells) and cellular immunity (by T cells). HSC: Hematopoietic stem cell; ILC: Innate Lymphoid Cell; NK cell: Natural Killer cell; H.Imm: Humoral immunity; C.Imm: Cellular immunity.

Figure 2

TME in anti- and pro-tumour conditions. The TME is a heterogeneous mass of tumour cells, stromal cells (such as MSC, CAF), blood vessels and immune cells. On the left, the cytokines secreted by the different types of immune cells are shown. Those released in anti-tumour activity are shown in green and those released in pro-tumour activity in red (in some cases the same cytokine has dual effect). On the other hand, on the right, TME-derived factors (which influence immune cell fate) in general, and their outcomes, accordingly, are shown, both in an anti-tumour and pro-tumour microenvironment. iNOS: inducible nitric oxide synthase; ROS/RNS: reactive oxygen species/reactive nitrogen species; TGF-β: transforming growth factor beta; CXCL9: C-X-C chemokine ligand 9; CCL22: C-C Motif Chemokine Ligand 22; IL-4: interleukin-4; IFN-γ: interferon gamma; TNF-α: tumour necrosis factor alfa; MMPs: matrix metalloproteinases; AREG: amphiregulin; TME: tumour microenvironment; ADCC: antibody-dependent cellular cytotoxicity; IDO: indoleamine 2,3-dioxygenase; VEGF: vascular endothelial growth factor F; PGE2: prostaglandin E2; EMT: epithelial-mesenchymal transition.

Figure 3

Anti- and pro-tumour microenvironment of DCs and CD8⁺ T cells. (A) Antitumour microenvironment: Antigen presentation by DCs via MHC-I to CD8⁺ T cells is depicted. For T cell activation to take place, apart from antigen presentation, co-stimulatory signals (DAMPs released by tumour cells, which are recognised by the PRRs of DCs and thus activated) and activating cytokines (represented by the blue round shapes) are necessary. Accordingly, activated DC can also promote CD8⁺ T cell by releasing IL-12 which induces IFN-γ production by CD8⁺ T cells. (B) Immunosuppressive microenvironment. However, factors such as tumour cells-derived IL-6 production or TAMs-derived IL-10 production (involved in inhibiting DC-derived IL-12) can negatively influence maturation, migration, differentiation and hence, function of DCs, downregulating them and give rise to a pro-tumour microenvironment. TGF-β, another factor present in TME, is able to convert effector T cells into Treg, creating an immunosuppressive environment. DAMPs: Damage-associated molecular patterns; PRRs: pattern recognition receptors; DC: dendritic cell; IL-12: Interleukin-12; IFN-γ (interferon gamma); TAMs: Tumour-associated macrophages.