Biology subjects

Gojkovic, M.

Publications and source records attributed to Gojkovic, M..

3 recordsLinked to original sources

bioRxiv2026

YAP/TEAD drives treatment-induced adaptive immunosuppression in EGFR-mutant lung cancer

Residual disease remains a major obstacle for achieving durable responses in patients treated with oncogene-targeted therapy. Drug-tolerant persister (DTP) cells emerging under treatment and persisting in residual tumors are considered to be the root of acquired resistance, yet their contribution to immune evasion in on-treatment tumors is poorly defined. Here, we show in the context of EGFR-mutant lung cancer that DTP cells actively contribute to the formation of an immunosuppressive tumor microenvironment during EGFR tyrosine kinase inhibitor (TKI) therapy. In syngeneic mouse models and in patients, EGFR TKI therapy leads to an accumulation of immunosuppressive macrophages, which is strictly treatment-dependent and fully reversible upon treatment cessation or progressive disease, respectively. Quiescent DTP cells directly drive the recruitment and immunosuppressive reprogramming of monocytes and macrophages through a YAP-driven secretome, and the DTP-reprogrammed monocytes suppress T cell proliferation and effector functions in vitro. Co-targeting YAP with a TEAD inhibitor ORM-47286 rewires the DTP secretome and inhibits macrophage reprogramming in vitro, and prevents immunosuppressive macrophage accumulation and improves the efficacy of EGFR TKI therapy in immunocompetent mouse models. Our findings highlight the previously unappreciated role of DTP cells in modulating the tumor microenvironment in on-treatment tumors, and position the treatment-induced YAP/TEAD activity in DTP cells as an important driver of adaptive immunosuppression during EGFR-targeted therapy.

cancer biology↗

bioRxiv2020

Modified HIF expression in CD8+ T cells increases anti-tumor efficacy

Adoptive transfer of anti-tumor cytotoxic T cells is a novel form of cancer immunotherapy, and a key challenge is to ensure the survival and function of the transferred T cells. Immune cell survival requires adaptation to different micro-environments, and particularly to the hypoxic milieu of solid tumors. The HIF transcription factors are an essential aspect of this adaptation, and we undertook experiments to define structural determinants of HIF that would potentiate anti-tumor efficacy in cytotoxic T cells. We created retroviral vectors to deliver ectopic expression of HIF-1ɑ and HIF-2ɑ in mouse CD8+ T cells, together or individually, and with or without sensitivity to their oxygen-dependent inhibitors Von Hippel-Lindau (VHL) and Factor Inhibiting HIF (FIH). We found that HIF-2ɑ, but not HIF-1ɑ, drives broad transcriptional changes in CD8+ T cells, resulting in increased cytotoxic differentiation and cytolytic function against tumor targets. We further found that a specific mutation replacing the hydroxyl group acceptor site for FIH in the HIF-2ɑ isoform gives rise to the most effective anti-tumor T cells after adoptive transfer in vivo. Lastly, we show that co-delivering an FIH-insensitive form of HIF-2ɑ with an anti-CD19 chimeric antigen receptor greatly enhances cytolytic function of human CD8+ T cells against lymphoma cells. These experiments provide a means to increase the anti-tumor efficacy of therapeutic CD8+ T cells via ectopic expression of the HIF transcription factor.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2019

Lactate potentiates differentiation and expansion of cytotoxic T cells

Exercise has a range of effects on metabolism. In animal models, repeated exertion reduces malignant tumour progression, and clinically, exercise can improve outcome for cancer patients. The etiology of the effect of exercise on tumour progression is unclear, as are the cellular actors involved. We show here that exercise-induced reduction in tumour growth is dependent on CD8+ T cells and that lactate, which is produced at high levels during exertion, increases proliferative capacity and cytotoxicity of CD8+ T cells. We found that at elevated levels lactate is used as a fuel during T cell activation. We further found that injection of lactate into animals can reduce malignant tumour growth in a dose-and CD8+ T cell-dependent manner. These data demonstrate that lactate can act to increase the anti-tumour activity of cytotoxic T cells, and in so doing, reduce cancer progression.

immunology↗