Polarized immune responses differentially regulate cancer development

Abstract

Tumor-associated immune responses assert varied responses toward developing neoplasms that can either act to eradicate malignant cells via engagement of potent cytotoxic programs or alternatively enhance tumor growth through release of multifunctional pro-tumor mediators. Seemingly paradoxical, these disparate activities reflect a continuum of polarization (or activation) states possible for distinct leukocyte subsets that demonstrate tissue, organ, and tumor selectivity. Herein, we review clinical and experimental studies investigating cellular and molecular mechanisms utilized by neoplastic tissues to alternatively polarize immune responses that favor either pro- or anti-tumor immunity.

Fig. 1. Polarization of immune responses during tumor development

Epithelial cancers develop through expansion of cells harboring mutations in key regulatory genes, i.e. initiated cells (A). Microenvironmental effectors, such as inflammation, promote (B) malignant conversion (C) of initiated cells. When an inflammatory response is triggered during initiation or promotion, antigen-presenting cells (APCs), such as dendritic cells and macrophages, take up tumor-associated antigens and present them (D) to naïve T helper (Th) cells. Depending on the context and the inflammatory microenvironment in which antigen presentation occurs, Th cells can become alternatively polarized. The process of immune polarization integrates a large number of microenvironmental signals (E) into one general outcome. Three discrete and mutually exclusive Th cell lineages, Th1, Th2, and Th17, have been defined. Th1 polarized immune responses (F) are associated with cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells and favor cancer regression. CTL-mediated tumor cell cytotoxicity can be inhibited through recruitment and/or conversion of natural or adaptive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) (G). Th2 and Th17 polarized immune responses both have been shown to promote tumor progression (H) by establishing chronic inflammation, e.g. through cytokine production and induction of humoral responses. Chronic inflammation can promote tumor progression in multiple ways, such as stimulation of tumor cell proliferation and dedifferentiation, activation of angiogenesis, and recruitment of Tregs and MDSCs, as well as through remodeling of extracellular matrix (ECM) and tissue basement membranes.