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Recruitment, phenotype and function of tumour-infiltrating regulatory T cells in the lung microenvironment

University of British Columbia

Despite the crucial role of regulatory T cells (Tregs) in the regulation of immunity toward innocuous antigens, these cells may contribute to the growth and metastasis of a variety of malignancies, either directly by production of cell growth and angiogenic factors, or indirectly by suppression of anti-tumour immunity. Tregs may support the development of both primary and metastatic tumours; however, the therapeutic inhibition of these cells is complicated by the presence of tissue-specific phenotypes and functions, which require further characterization based on the type of cancer and local microenvironment. We have observed that Treg accumulation in primary and metastatic tumours in the lung microenvironment is significantly increased in a clinical and pre-clinical setting, respectively. Therefore, in this thesis we hypothesize that Tregs promote tumour growth in the lungs. To explore this hypothesis, we examine the phenotype and function of tumour-infiltrating Tregs and inhibit their homing to observe the impact on tumour growth. Herein, we report that Tregs isolated from mice bearing metastatic tumours are functionally immune suppressive and enriched for expression of the homing receptor C-C chemokine receptor type 5 (CCR5). Inhibition of Tregs with the CCR5 antagonist, Maraviroc, reduced CCR5⁺ Treg accumulation and tumour burden in the lungs. We identify that Tregs accumulate during early stage disease in lung cancer patients, and show that oncogene-induced chemokine production promotes Treg migration. Further, we identify that oncogene-induced Treg migration is significantly reduced by antibody-mediated neutralization of the CCR5 ligand, CCL5 ex vivo. Finally, we report that a subset of Tregs expressing the interleukin 1 family receptor, ST2, may directly promote tumour progression by production of the growth factor amphiregulin (AREG) in response to the cognate ligand, IL-33 in the lung microenvironment. Taken together, these results provide evidence that Tregs are important contributors to tumour development in the lung microenvironment and identify signaling axes required for their recruitment and function. Our findings highlight the viability of homing inhibitors as an alternative mechanism to systemically ablating Tregs for the treatment of lung metastases.

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2018-04-04

Attribution-NoDerivatives 4.0 International

http://hdl.handle.net/2429/65118

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nd/4.0/