Lymphocytes in cancer development: polarization towards pro-tumor immunity

Abstract

The classic view that the role of immune cells in cancer is primarily one of tumor rejection has been supplanted by a more complex view of leukocytes having both pro- and anti-tumor properties. This shift is due to the now well recognized capabilities of several myeloid cell types that foster pro-tumor programming of premalignant tissue, as well as the discovery that subsets of leukocytes also suppress development and effector functions of lymphocytes important for mediating anti-tumor immunity. In this review, we focus on the underappreciated role that T lymphocytes play in promoting tumor development. This includes, in addition to the role of T regulatory cells, a role for natural killer T cells and CD4(+) T helper cells in suppressing anti-tumor immunity and promoting cancer growth and metastasis.

Figure 1. T cell lineages and subsets

Successful rearrangement and expression of a TCR determines lineage commitment between γδ and αβ T cells. Recognition by αβ T cells of MHCI, MHCII, or CD1d drives CD8⁺, CD4⁺ or NKT cell development, respectively. Strong recognition of peptide:MHCII complexes by CD4⁺ cells drives natural T_Reg cell development in the thymus, otherwise CD4⁺ T cells differentiate into T_H1, T_H2, T_H17 or inducible T_Reg cells following activation in the periphery, with polarization directed by IL-4, IL-6, IL-12 and TGF-β. Type I NKT cells are defined by expression of specific α-chain regions (Vα14-Jα18 in mice, Vα24-Jα18 in humans), but the reason for functional differences between type I and type II NKT cells is unclear.

Figure 2. T cell-derived cytokines regulate pro- and anti-tumor immunity

NK cells, γδ T cells, and CD8⁺ CTLs mediate anti-tumor immunity by inducing cell death in neoplastic cells. The cytotoxic effector functions of these cells are supported by IFNγ released from T_H1 and type I NKT cells, as well as by self-production of IFNγ that further drives T_H1 polarization. T_H2 polarization opposes T_H1 polarization, and the release of IL-4 and IL-13 by both T_H2 and type II NKT cells can direct macrophages towards an M2 phenotype. Macrophages polarized by IL-4 promote metastasis through the release of EGF, while production of TGFβ suppresses the immune response directly, or indirectly through promotion of T_Reg development. In the presence of IL-6, TGFβ can also promote T_H17 polarization. IL-17 induces the production of IL-6 by tumor cells, which both promotes tumor cell growth and further drives T_H17 polarization, while IL-21 has been shown to enhance CTL effector function. Multiple cell types and pathways have been omitted for clarity.