The Treg/Th17 Paradigm in Lung Cancer

Abstract

Pathogenic mechanisms underlying the development of lung cancer are very complex and not yet entirely clarified. T lymphocytes and their immune-regulatory cytokines play a pivotal role in controlling tumor growth and metastasis. Following activation by unique cytokines, CD4+ T helper cells differentiate into Th1, Th2, Th17, and regulatory T cells (Tregs). Traditionally, research in lung cancer immunity has focused almost exclusively on Th1/Th2 cell balance. Recently, Th17 cells and Tregs represent an intriguing issue to be addressed in lung cancer pathogenesis. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against tumor cells. Th17 cells directly or via other proinflammatory cytokines modulate antitumor immune responses. Notably, there is a close relation between Tregs and Th17 cells. However, the possible interaction between these subsets in lung cancer remains to be elucidated. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent a useful tool for lung cancer treatment in the future. The purpose of this review is to discuss recent findings of the role of these novel populations in lung cancer immunity and to highlight the pleiotropic effects of these subsets on the development and regulation of lung cancer.

Cytokine-induced killer cell therapy for modulating regulatory T cells in patients with non-small cell lung cancer

“…CD4 + CD25 + FOXP3 + Tregs account for 5-10% of all T lymphocytes in healthy individuals (23). Evidence suggests that Tregs contribute to immune suppression by dampening the antitumor immunity elicited by CD4 + T cells, CD8 + T cells, dendritic and NK cells (24)(25)(26)(27). Treg accumulations in tumors and peripheral blood have been linked to unfavorable disease outcomes of tumor invasion, recurrence and shortened survival for many human solid tumors, including hepatocellular carcinoma, ovarian carcinoma, pancreatic ductal carcinoma, cervical cancer, NSCLC and breast cancer (28)(29)(30)(31)(32)(33).…”

Anti-cancer activity of dose-fractioned mPE +/− bevacizumab regimen is paralleled by immune-modulation in advanced squamous NSLC patients

“…T reg s, whose activation is under control of CTLA-1 checkpoint, have the specific ability to attenuate the extent of cancer associate immuneresponse and represents a common mechanism of immuneescape for cancer cells (26)(27)(28)(29). IL-17A is able to promote A B the switch of inactive T reg s in highly suppressive subsets that, in turn, can inhibit all the attempts of immune-system and tumor-specific CTLs to counteract tumor growth and development (29)(30)(31)(32) another very active CTL subset expressing the L selectin (CD62L), a trans-membrane protein which allows the binding to the specific receptor on tumor vessels and the consequent extravasation in the tumor sites (37). In our patients, we also found a significant increase of peripheral DCs expressing CD83 and CD80, a very efficient antigen presenting cell linage able to uptake and process antigen released by tumor tissues exposed to the cytotoxic drugs (38).…”

Permissive/Protective Interplay of Microbiota with T Cell Adaptive Immune Response in Colon Cancer

“…On the other hand, CD4+ T cells, differentiating into Th2 cells, express GATA3 and Stat6 and produce more IL-4, IL-5, and IL-13. In addition, CD4+ Th2 cells are part of a type-2 immune response, i.e., a type of immunity which is mainly involved in the removal of helminthes and extracellular parasites and facilitates B-cell antibody secretion (3)(4)(5).…”

“…Recent studies have progressively revealed the role of recently recognized CD4+ subsets, i.e., Th17 cells and T regulatory cells (Tregs), in immunity, particularly at mucosal surfaces where large and diverse numbers of microbes (also known as microbiomes) reside (5,6). Th17 cells, as an inflammatory subset of CD4+ cells, are the main source of IL-17A, IL-17F, and IL-22 (7).…”

“…Tregs express fork-head lineagespecific transcription factor (FoxP3) proteins and are able to secrete immunomodulatory cytokine, IL-10 (10). In addition to an imbalance in Th1/Th2 cells, a dysregulated immune response, related to Th17 and FoxP3+ Tregs, has been linked to certain types of cancer, particularly colon cancer (3)(4)(5).…”