Navarrete Sanchez, Mariela Ivonne; (2025) Deciphering the role of the lung tumour microenvironment in the activity of regulatory T cell-depleting antibodies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Regulatory T cells (Tregs) accumulate in the tumour microenvironment (TME) and suppress anti-tumour immunity, making them an attractive target for cancer immunotherapy. However, clinical trials of Treg-depleting antibodies have so far produced inconsistent results, with limited clinical benefit and unclear mechanisms of response or resistance. Emerging evidence suggests that features of the TME may critically shape therapeutic outcomes. This thesis investigates how the composition of the lung TME influences the performance of Treg-depleting antibodies, with a particular focus on Fc gamma receptor (FcgR)-mediated mechanisms of action. Using lung and subcutaneous tumour models, we show that Treg-depleting antibodies efficiently eliminate Tregs in subcutaneous tumours but are markedly less effective in lung tumours. This discrepancy correlates with distinct FcgR expression profiles within the local myeloid compartment. In subcutaneous tumours, FcgR-expressing innate effector cells are abundant, enabling robust antibody-dependent cellular cytotoxicity/phagocytosis. In contrast, the lung TME exhibits reduced expression of activating FcgRs, which limits the efficacy of Fc-mediated Treg depletion. To overcome this, we employed a novel therapeutic strategy using lipid nanoparticles encoding cyclic GMP-AMP synthase (cGAS-LNPs) to activate the STING pathway and modulate lung-resident myeloid cells. cGAS-LNP treatment increased the expression of activating FcgRs, enhanced CD25 surface expression on Tregs, and primed the lung TME for antibody-mediated Treg-depletion. When combined with a non-IL-2 blocking anti-CD25 antibody (aCD25NIB), cGAS-LNPs restored Treg depletion in the lung, promoted CD8+ T cell activation, and improved tumour control. These findings highlight the importance of tumour site-specific FcgR landscapes in determining antibody efficacy and demonstrate that STING-driven myeloid modulation can broaden the therapeutic window for Treg-targeting strategies in otherwise treatment- resistant tumour environments.

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