TSLP, Inflammation, & Cancer

Chronic inflammation and infiltration of T lymphocytes are common in the tumor microenvironment.¹ One of the main questions that researchers are trying to answer is whether these T cells inhibit or promote cancer progression. While it is possible that T cells present in the tumor microenvironment have an immunosurveillance function that inhibits transformed cells from establishing tumors, these cells may also promote tumor cell tolerance and metastasis. Research suggests that the T cell-induced effects on tumor progression depend on tumor cell cross talk with the surrounding stroma, dendritic cells, myeloid cells, and the types of T cells involved.¹ Recent studies indicate that thymic stromal lymphopoietin (TSLP) may be a key molecule contributing to the cross talk between these cell types in breast and pancreatic cancers.^{2, 3, 4}

As its name implies, TSLP was first identified as a molecule secreted by the thymic stroma that plays a role in T cell and B cell development. Since that time, several roles for TSLP outside the thymus have been identified.⁵ TSLP is primarily produced by epithelial cells in the gut, lungs, and skin, and predominantly acts on T cells that are involved in barrier immunity. It can directly affect T cell functions in mouse due to expression of the TSLP receptor heterodimer (TSLP R/IL-7 R alpha) on the mouse T cell surface; in humans, however, TSLP appears to act mainly through monocyte-derived dendritic cells (MoDCs).⁶ In both species, TSLP is a potent activator of immature MoDCs.^{5, 6} TSLP-stimulated MoDCs produce chemokines such as CCL17/TARC and CCL22/MDC, which attract naïve T cells to the area, and OX40 Ligand, which regulates T cell functions.⁷ TSLP stimulation of naïve CD4⁺ T cells, either directly via TSLP R or indirectly via engagement of T cell OX40 by OX40 Ligand on TSLP-treated DC, induces a specialized Th2 polarization. These Th2 cells abundantly produce pro-inflammatory cytokines such as IL-4, IL-13, and TNF-alpha but not anti-inflammatory cytokines such as IL-10.^{5, 7} This polarization pathway depends on the absence of IL-12 which, when present, redirects MoDCs to stimulate Th1 differentiation.^{2, 7} The specialized inflammatory Th2 cells may be involved in barrier site allergic reactions, such as asthma and atopic dermatitis.⁵

Three research groups have recently identified a mechanism by which cancer cells and associated stromal cells can subvert this pathway to promote tumor progression.^{2, 3, 4} These studies find that TSLP is produced by human and mouse breast cancer cells, and by pancreatic cancer-associated fibroblasts activated by tumor-derived TNF-alpha and IL-1 beta.^{2, 3, 4} In the tumor microenvironment, as in barrier tissues, TSLP induces maturation of MoDCs, which then increase production of OX40 Ligand, CCL17/TARC, and CCL22/MDC.^{2, 3} Engagement of OX40 polarizes naïve T cells to differentiate into Th2 cells that produce IL-13 and TNF-alpha.² Neutralization of TSLP or OX40 Ligand, TSLP deletion, or downregulation of TSLP expression by shRNA dramatically decreases the rate of breast cancer progression, lung metastases, and pancreatic tumor growth.^{2, 3, 4}

Previous work suggests several possible mechanisms by which MoDCs and inflammatory Th2 cells promote tumor progression and metastasis. One study found that breast cancer-associated Th2 cells enhance the activity of alternatively activated M2 tumor-associated macrophages (TAMs).⁸ M2 TAMs secrete EGF and TGF-beta, enhance the growth of breast cancer cells, support angiogenesis, and promote invasion.^{1, 8} A second study found that IL-13 secreted by inflammatory Th2 cells may directly stimulate breast cancer cells, promoting tumor establishment and metastasis.⁹ Several studies have also found that CCL22/MDC-producing DC can recruit regulatory T (Treg) cells that promote tumor tolerance and inhibit NK cell- and CTL-mediated killing of tumor cells.^{2, 3, 10, 11} These Treg cells are required for lung metastasis of breast cancer cells.^{3, 11} Interfering with the TSLP-OX40L-IL-13 axis in the cancer microenvironment thus presents an interesting potential target for therapy.²

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TSLP Mediates Cross Talk Between Cancer Cells and the Immune System. Tumor cells or cancer-associated fibroblasts produce TSLP that promotes immature DC (iDC) maturation and production of CCL17, CCL22, and OX40 Ligand by monocyte-derived dendritic cells (MoDCs). The chemokines attract naïve T cells and regulatory T (Treg) cells, while OX40 Ligand induces polarization of inflammatory Th2 cells. Inflammatory cytokines (IL-13, IL-4, TNF-alpha) produced by Th2 cells induce macrophage polarization to M2 type tumor-associated macrophages (M2-TAM). EGF and TGF-beta secreted by M2-TAMs and IL-13 produced by Th2 cells promote tumor establishment and metastasis.

References

1. Grivennikov, S.I. et al. (2010) Cell 140:883.
2. Pedroza-Gonzales, A. et al. (2011) J. Exp. Med. 208:479.
3. Olkhanud, P.B. et al. (2011) J. Immunol. 186:5656.
4. De Monte, L. et al. (2011) J. Exp. Med. 208:469.
5. Ziegler, S.F. & D. Artis (2010) Nat. Immunol. 11:289.
6. Ziegler, S.F. & Y-J. Liu (2006) Nat. Immunol. 7:709.
7. Ito, T. et al. (2005) J. Exp. Med. 202:1213.
8. DeNardo, D.G. et al. (2009) Cancer Cell 16:91.
9. Aspord, C. et al. (2007) J. Exp. Med. 204:1037.
10. Gobert, M. et al. (2009) Cancer Res. 69:2000.
11. Olkhanud, P.B. et al. (2009) Cancer Res. 69:5996.

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