Innate γδT17 cells convert cancer-elicited inflammation into immunosuppression through myeloid-derived suppressor cells

Abstract

Chronic inflammation has been linked to cancer development and metastasis. We have recently demonstrated that γδ T cells are the major cellular source of IL-17 (γδT17) and accumulation of γδT17 cells correlates with human colorectal cancer progression through recruitment and expansion of myeloid-derived suppressor cells, thus converting tumor-elicited inflammation into immunosuppression.

Chronic inflammation has an intimate relationship with cancer initiation, progression, and metastasis.¹ Cancer-related inflammation is mediated by tumor-infiltrating leukocytes, stromal cells, and cancer cells. These tumor cells can secrete inflammatory cytokines, chemokines, metabolites, and other tumor-promoting molecules such as prostaglandin E2 (PGE2), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF).² Among these, the cytokine IL-17 has recently drawn more attention due to its role in tumor-related inflammation.^3-5

Two critical questions were particularly addressed by these recent studies. The first question is related to the role of IL-17 in tumor promotion. Although prior research has evinced a tumor-protective role for IL-17,⁶ more recently it has clearly been demonstrated that IL-17 is typically a tumor-promoting cytokine.^3-5,7 For example, in murine hepatocellular carcinoma models IL-17 promotes cancer progression.⁵ This effect is not through direct stimulation of malignant cells, rather via impaired antitumor CD8⁺ T-cell responses. The frequency of interferon γ (IFNγ)-producing CD8⁺ T cells is significantly higher in IL-17A knockout mice (IL-17^−/−). In addition, CD8⁺ T cells from IL-17^−/− mice exhibit enhanced cancer killing activity. We found that IL-17 is significantly increased both at the level of transcription and protein expression in human colorectal cancer (CRC).⁴ The levels of IL-17 correlate with the clinicopathological features of tumors, suggesting a tumor-promoting role for IL-17 in human CRC. In support, it appears that IL-17 is one of the main driving chemoattractant forces for the recruitment of myeloid-derived suppressor cells (MDSCs). We found that in human CRC, polymorphonuclear (PMN)-MDSCs predominate tumor-infiltrating myeloid cells and are abundant in patient tumors. Further in vitro studies showed that neutralizing IL-17 monoclonal antibody (mAb) significantly decreased PMN-MDSC proliferation and survival.⁴ In murine tumor models, IL-17A also promotes MDSC tumor infiltration in a (C-X-C) motif chemokine receptor 2 (CXCR2)-dependent manner.⁵ In addition, IL-17 directly stimulates tumor cells to upregulate chemokine expression such as the (C-X-C) motif chemokine ligands CXCL5 and CXCL12, which may further promote MDSC accumulation within the tumor microenvironment.⁵ Furthermore, IL-17 also enhances the immunosuppressive function of MDSCs. Finally, IL-17 has been found to mediate resistance to anti-VEGF therapy in multiple types of cancer.³ Taken together, IL-17 pleiotropically promotes tumor progression mainly via the recruitment and accumulation of MDSCs, thus converting tumor-elicited inflammation into immunosuppression and promoting angiogenesis.

The second question addressed the cellular source of IL-17 within the tumor microenvironment. Previous studies with animal tumor models have considered αβ T helper 17 (Th17) cells as the major IL-17 producer⁸ In our study of human CRC, we used cytofluorimetric analysis to demonstrate that innate γδ T cells are the major cellular source of IL-17.⁴ γδT17 cells in human CRC predominantly exhibit a terminally differentiated phenotype (CD45RA⁺CD27⁻) and express CCR6 and CD161. In regards to the T-cell receptor complex, γδT17 cells express mainly Vδ1, which is different from regulatory Vδ2⁺ γδ T cells prevalent in human breast cancers.⁹ In addition, we showed that the frequency of tumor-infiltrating γδT17 cells is substantially and positively correlated with advancing TNM stages, lesion size, and metastasis.⁴ In murine hepatocellular carcinoma models, Vγ4 γδ T cells were also identified as the main source of IL-17.⁵ Depletion of Vγ4 T cells significantly attenuated IL-17 production, thereby leading to reduced tumor burden. In TCRδ^−/- mice, reconstitution of Vγ4 γδ T cells significantly enhanced tumor growth. These studies provide direct evidence suggesting that γδT17 cells are the major cellular source of IL-17, at least in human CRC and murine hepatic cancer models. It also formally establishes the pathogenic role of γδT17 cells in tumor development. It is worth noting that γδT17 cells not only produce large amounts of IL-17 but also secrete other cytokines including IL-8, tumor necrosis factor α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF), signals that further promote MDSC migration, expansion, and survival.⁴

How do γδT17 cells get activated? Innate γδ T cells are considered ‘pre-committed’ or ‘pre-programmed’ cells. However, accumulating evidence suggests that these cells are also subject to peripheral regulation.¹⁰ In human CRC, γδT17 cells can be activated by inflammatory dendritic cells (DCs). We showed that microbial product-activated DCs promote γδT17 cell polarization in an IL-23-dependent manner.⁴ It appears that epithelial barrier failure caused by tumor initiation and progression results in commensal bacterial product release in CRC tumors, which in turn activates DCs to stimulate γδT17 cell expansion and activation. However, it is unclear how γδT17 cell activation is initiated in other tumor models, particularly in tumors that are not related to commensal microbes. One possible pathway is through tumor-elicited MDSCs, as MDSCs have been shown to secrete IL-23 and IL-1β in murine hepatic cancer models.⁵ Another possibility is that danger-associated molecular patterns (DAMPs) triggered by tumor progression or released by cancer cells could activate antigen-presenting cells (APC) to secrete cytokines IL-23 and IL-1β, thus promoting γδT17 cell expansion and activation. Based on these findings, we propose a feed-forward model, which depicts the role of γδT17 cells in cancer progression (Fig. 1). Innate γδT17 cell expansion and activation may be driven by cancer initiation and progression via 3 possible pathways: i) release of DAMPs by apoptotic tumor cells or tumor-mediated processes; ii) recruitment and accumulation of MDSCs in the tumors driven by tumor-secreting factors; and iii) epithelial barrier disruption, such as occurs in the colon resulting in microbial product release. All of these routes culminate in IL-23 and IL-1β production, thus promoting γδT17 cell polarization. γδT17 cells secrete large amounts of cytokines, including IL-17, IL-8, GM-CSF, and TNFα, all of which directly chemoattract MDSCs to the tumor site and stimulate their expansion. Alternatively, these cytokines may act indirectly by stimulating malignant cells to secrete chemokines soliciting MDSC recruitment, thereby forming an amplification loop. Thus γδT17 cells transform cancer-elicited inflammation into immunosuppression via acting on MDSCs and subsequently inhibiting antitumor CD8⁺ T-cell responses. These findings reveal that γδT17 cells are crucial players in cancer progression, and the eradication of these tumor-promoting cells could potentially form the basis of an effective cancer therapy.

Figure 1.

Innate γδT17 cells convert cancer-elicited inflammation into immunosuppression through MDSCs. Activation and expansion of γδT17 cells in the tumor, stimulates the recruitment and accumulation of MDSCs leading to immunosuppression and tumor progression. DAMP, danger-associated molecular pattern; MDSC, myeloid-derived suppressor cell; DC, dendritic cell.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.