Helper T Cells and Cancer-Associated Inflammation: A New Direction for Immunotherapy?

Th2 Cells in Breast Cancer

Th2 cells produce IL-4, −5, and −13 and regulate immune responses against extracellular parasites, such as helminthes. Th2 cells are also key in allergic inflammation by promoting maturation and tissue recruitment of eosinophils and basophils, as well as IgE production by B cells. Th2 cells are regulated by the innate immune system using IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) cytokines.

There is increasing evidence to support an association of Th2 cells with the tumor microenvironment in breast cancer. High levels of Th2 cell-derived cytokines were reported in the sera of different types of human breast cancer patients, and the levels of IL-4 and the numbers of tumor-infiltrating CD4⁺ T cells were found to positively correlate with tumor progression and metastasis to sentinel lymph nodes (Kohrt and others 2005; Mantovani and others 2008; Pedroza-Gonzalez and others 2011), highlighting the clinical relevance of Th2 cells in the pathogenesis of human breast tumors.

Preclinical studies have also demonstrated an important role of Th2 cells in controlling the progress and metastasis of tumors (Coussens and others 2013). IL4ra deficiency, which inhibited both IL-4 and IL-13 signaling, resulted in decreased metastasis without affecting primary tumor growth in the PyMT breast cancer model (DeNardo and others 2009). Through secreting IL-4, Th2 cells may modulate the polarization and effector function of type 2 macrophages (M2) in the tumor microenvironment. For example, IL-4 was reported to promote the growth, angiogenesis, and invasion of tumor cells by inducing cathepsin activity in macrophages (Gocheva and others 2010). IL-4 may also potentiate pulmonary metastasis through M2 macrophages to activate epidermal growth factor receptor signaling in malignant mammary epithelial cells (DeNardo and others 2009).

Th2 cell development and function are regulated by the innate cytokines IL-25 and IL-33. Preclinical breast cancer models have also revealed their important function in cancer development and metastasis. ST2 is a member of the IL-1 receptor family with IL-33 as its natural ligand. The IL-33/ST2 pathway regulates Th1/Th2 immune responses in autoimmune and inflammatory conditions. In a mammary carcinoma model, deletion of ST2 was reported to attenuate tumor growth and metastasis, which was accompanied by increased serum levels of IL-17, IFN-γ, and TNF-α and decreased IL-4 (Gao and others 2015). Tumor-bearing Il1rl1 ^−/− mice had significantly higher percentages of activated natural killer (NK) and CD8⁺ T cells in vitro. In vivo depletion of CD8⁺ or NK cells revealed a key role for NK cells in enhanced antitumor immunity in Il1rl1 ^−/− mice. In addition, IL-25, another Th2 promoting cytokine, was reported to be highly expressed in human and murine breast cancer (Jiang and others 2016). IL-25 blockade by an antagonistic antibody, interestingly, did not reduce the growth of the primary tumor but inhibited metastasis, consistent with the data on IL-4R knockout mice in the same model. Moreover, IL-25 blockade was found to decrease Th2 and M2 macrophages in the primary tumor microenvironment.

Thus, Th2 cells and their promoting cytokines in breast cancer instruct a microenvironment that involves M2 microphages to promote tumor metastasis and inhibits cytotoxicity by the immune cells.

Th17 Cells in Cancer

Autoimmune inflammation has long thought to be mediated by Th1 cells until the discovery of Th17 cells in 2015 (Dong 2006). Th17 cells secrete IL-17, IL-17F, and IL-22 and play important roles in acute and chronic tissue inflammation. Targeting IL-17 has achieved great efficacy in diseases such as psoriasis (Dong 2014; Lai and Dong 2015). Th17 cells are regulated by innate system-derived pro-inflammatory cytokines such as IL-6, IL-23, and IL-1.

Th17 cells have been reported in many types of human cancers, which impacted prognosis of the patients. For example, increased Th17 cells were associated with improved prognosis of patients with oropharyngeal squamous carcinoma (Punt and others 2016) and salivary gland tumors (Haghshenas and others 2015). In contrast, patients with melanoma and early stage ovarian cancer and malignant pleural effusions with increased Th17 cells had better survival (Kryczek and others 2009a).

Th17 cell development and function are regulated by IL-23. IL-23 was first found to be highly expressed in many types of tumors (Langowski and others 2006). Genetic deletion or antibody-mediated elimination of IL-23 increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Finally, transplanted tumors are growth-restricted in hosts depleted for IL-23 or in IL-23-receptor-deficient mice.

However, the direct roles of Th17 cells in tumor are complex and there have been reports on the promoting or inhibiting effects for these cells in tumorigenesis. In melanoma model B16, deletion of IL-17 resulted in increased tumor burden, whereas transfer of Th17 cells inhibited tumor growth (Kryczek and others 2009b; Martin-Orozco and others 2009). Furthermore, it was reported that Th17 cells promoted CD8⁺ T cell activation and function by enhancing dendritic cell recruitment and antigen presentation.

In contrast, in several cancer models with strong inflammatory components, deletion or blockade of IL-17 resulted in inhibition of cancer development. In lung cancer model, it was found that IL-17 deficiency or blockade resulted in decreased tumor growth (Chang and others 2014). IL-17 was required for the recruitment of MDSC, proliferation of tumor cells, and the angiogenesis within the tumor microenvironment. Depletion of MDSC had similar effects as IL-17 inhibition in this model, suggesting that IL-17 may regulate the tumor microenvironment, in part, through MDSC. “Th17 expression signature” in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival (Grivennikov and others 2012). IL-17 was found to be required for a murine model of colon cancer, while IL-17F deficiency modestly increased tumor growth (Tong and others 2012). Moreover, IL-23 signaling promotes tumor growth and progression and development of an intra-tumor IL-17 response (Grivennikov and others 2012). IL-23 produced by tumor-associated myeloid cells is regulated by microbial products, as a result of impaired tight junction in the tumor colon tissues.

Th17 cells thus may have pro- or antitumor effects depending on the context. It is possible that in poorly immunogenic model, IL-17 facilitates immune activation against tumor. However, in tumors associated with chronic inflammation, IL-17 may be used by the tumor cells to create a permissive environment. Further analysis of other immune-profilings in the tumor microenvironment may help us understand and guide more personalized therapy in targeting this pathway in tumors.

Conclusion

Th2 and Th17 cells play important roles in cancer. The data thus far have suggested crucial function of these cells to sustain chronic inflammation and shape up the microenvironments necessary for tumor development. We are just in the beginning to understand the function and regulation of these CD4⁺ T cells associated with cancer development. More studies, especially on primary human tumors, are needed to understand the issues better and guide us in precision medicine. It is anticipated that targeting pro-inflammatory T cells may emerge as additional approaches in immunotherapy against cancer.