Immune surveillance: a balance between protumor and antitumor immunity

Abstract

Precancerous and malignant cells can induce an immune response which results in the destruction of transformed and/or malignant cells, a process known as immune surveillance. However, immune surveillance is not always successful, resulting in 'edited' tumors that have escaped immune surveillance. Immunoediting is not simply because of the absence of antitumor immunity, but is because of protumor immunity that blocks antitumor adaptive and innate responses, and promotes conditions that favor tumor progression. Several immune protumor effector mechanisms are upregulated by chronic inflammation, leading to the hypothesis that inflammation promotes carcinogenesis and tumor growth by altering the balance between protumor and antitumor immunity, thereby preventing the immune system from rejecting malignant cells, and providing a tumor-friendly environment for progressive disease.

Figure 1

Tumor immunity is a balance between immune mediators that promote tumor progression vs. mediators that promote tumor rejection. CD4⁺ T regulatory cells, Type 2 CD4⁺ T cells, Type 2 natural killer T cells, myeloid-derived suppressor cells, M2 or tumor-associated macrophages, B cells, and possibly mast cells promote tumor progression, while CD8⁺ T lymphocytes, type 1 CD4⁺ T lymphocytes, natural killer, type 1 natural killer T cells, M1 macrophages, and immune killer dendritic cells promote tumor destruction.

Figure 2

CD4⁺ T lymphocytes are induced by cytokines to produce cytokines that either promote tumor progression or mediate tumor elimination. Type 1 CD4⁺ T cells are induced by IL-12 and IFNγ to produce IFNγ which promotes the differentiation and expansion of CD8⁺ T cells that are cytotoxic for tumor cells. In contrast, IL-4 polarizes CD4⁺ T cells towards a type 2 phenotype that produces IL-4, IL-5, and IL-13 which help B cells produce antibodies, thereby directing immunity away from a tumor-rejecting type 1 response. Under the influence of transforming growth factor β, CD4⁺ T cells develop into T regs that actively block tumor immunity by suppressing tumoricidal CD8⁺ T cells. Recently identified Th17 cells are induced by IL-23 to produce IL-17, which in turn induces cytokines and chemokines that promote inflammation. The resulting inflammatory mediators may contribute to tumor progression by up-regulating immune suppressive cells of the adaptive and innate immune systems (see figure 4)

Figure 3

Macrophages are differentially activated by different cytokines or other factors and become either tumor-promoting or tumoricidal. Classically-activated or M1 macrophages produce high levels of type 1 cytokines that promote a tumor-rejecting type 1 response as well as factors such as inducible nitric oxide synthase which are cytotoxic for tumor cells, and low levels of type 2 cytokines. In contrast, alternatively-activated or M2 macrophages produce high levels of cytokines that polarize immunity towards a tumor-promoting type 2 response, and low levels of cytokines that promote a tumor-destructive type 1 response. Some of the molecules produced by M2 macrophages attract additional pro-inflammatory mediators to the tumor site, thereby amplifying the inflammatory microenvironment.

Figure 4

Inflammation may regulate the balance between pro- and anti-tumor immunity by inducing the development of immune mediators that promote carcinogenesis and tumor progression. Activated B cells or possibly CD4⁺ Th17 cells can contribute to an existing state of chronic inflammation or de facto induce inflammation which results in the increase and activation of M2 macrophages, CD4⁺ T regulatory cells, and myeloid-derived suppressor cells. These immune suppressive cells then block immune surveillance, preventing the host’s immune system from rejecting pre-malignant cells. In the presence of established tumor, the inflammatory environment is maintained by B cell-secreted factors and possibly CD4⁺ Th17 cells, and by additional factors produced by the tumor cells and by host cells attracted to the tumor site. This increased inflammation induces the accumulation and activation of additional M2 macrophages and myeloid and T suppressor cells which fuel tumor progression.