Distinct T helper cell-mediated antitumor immunity: T helper 2 cells in focus

Abstract

The adaptive arm of the immune system is crucial for appropriate antitumor immune responses. It is generally accepted that clusters of differentiation 4⁺ (CD4⁺) T cells, which mediate T helper (Th) 1 immunity (type 1 immunity), are the primary Th cell subtype associated with tumor elimination. In this review, we discuss evidence showing that antitumor immunity and better prognosis can be associated with distinct Th cell subtypes in experimental mouse models and humans, with a focus on Th2 cells. The aim of this review is to provide an overview and understanding of the mechanisms associated with different tumor outcomes in the face of immune responses by focusing on the (1) site of tumor development, (2) tumor properties (i. e., tumor metabolism and cytokine receptor expression), and (3) type of immune response that the tumor initially escaped. Therefore, we discuss how low-tolerance organs, such as lungs and brains, might benefit from a less tissue-destructive immune response mediated by Th2 cells. In addition, Th2 cells antitumor effects can be independent of CD8+ T cells, which would circumvent some of the immune escape mechanisms that tumor cells possess, like low expression of major histocompatibility-I (MHC-I). Finally, this review aims to stimulate further studies on the role of Th2 cells in antitumor immunity and briefly discusses emerging treatment options.

Keywords: Adaptive immunity; Antitumor immune response; Cancer; Immunogenetics; Immunology; Immunotherapy.

Graphical abstract

Figure 1

Major factors driving T helper 2 (Th2) cell-mediated antitumor immune responses. (A) Low-tolerance organs, such as the lungs and brain, are highly susceptible to secondary tissue damage induced by immune responses, especially Th1-mediated cytotoxicity. In this sense, it is hypothesized that some tissues are intrinsically prone to Th2-mediated responses to control excessive tissue damage, a feature that can also be important to antitumor immunity in these sites. (B) Different metabolic requirements from tumor cells, even those that arose in the same site, can also explain a successful Th2-mediated immune response. For example, arginine depletion by M2 macrophages, differentiated in a Th2-dependent manner, led to tumor elimination in a mouse model of myeloma. (C) Immune escape mechanisms from Th1-mediated antitumor immune responses, such as low expression of major histocompatibility complex class I (MHC-I) molecules by tumor cells, can be circumvented by a change in the subset of T lymphocytes to Th2 cells. In these settings, cluster of differentiation (CD)8⁺ T cells can drive tumor elimination indirectly, after eosinophil infiltration. (D) At last, Th2 cells inhibit tumorigenesis and restrict tumor development after impairment of epithelial-mesenchymal transition and induction of terminal differentiation of breast cancer cells..