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Melese, Etienne

University of British Columbia

The immune response to solid tumours involves a complex interplay of both tumour-promoting immunosuppression and tumour inhibition via targeted cell killing. As tumour development progresses, immunosuppression occurs in the tumour microenvironment (TME) and killer CD8⁺ T cell activity can become inhibited by checkpoint receptor engagement. Current immune checkpoint inhibitors (ICI) are only effective in a subset of lung cancer patients and alternate immune evasion strategies can render these therapeutics less successful. To better understand mechanisms behind alternate immune evasion, this thesis examined whether tumour cell-secreted chemokines, circulating immune cells, and CD4⁺ tissue resident memory T cells (CD4⁺ Trm) can shape immunosuppression in the TME. In Chapter 3, driver oncogenes in lung cancer cells were shown to induce production of the chemokine, CCL5. Mouse models with tumour cell CCL5 knockdown had decreased regulatory T cells (Tregs), display reduced evidence of T cell exhaustion and reduced lung tumour burden. This shows that tumour cell CCL5 production contributes to an immune suppressive environment in the lungs. Chapter 4 details a longitudinal, peripheral blood-based immunophenotyping study of stage IV NSCLC patients treated with anti-PD-1 ICI. This study identified several innate and adaptive immune cell populations, markers of interest, and cytokines that were altered pre-treatment or during ICI in a patient with durable clinical benefit compared to early progressors. These findings will help focus future, larger studies on peripheral blood biomarkers of response to ICI. Chapter 5 assessed CD4⁺ Trm cells presence, location, and potential function in lung cancer. We established that both genetically engineered and syngeneic mouse models of lung cancer had increased CD4⁺ Trm cells with distinct expression of checkpoint programmed death receptor-1 (PD-1), Th1 or Th2 transcriptional profiles, and type-1 cytokine production. In NSCLC patients, transcriptomic signatures of CD4⁺ Trm cells correlated with improved survival. In summation, the data details how tumour cell oncogenic signaling-induced CCL5 can contribute to immunosuppression in the TME, that longitudinal alteration to circulating immune cells and cytokines distinguished a patient with durable response to ICI and that populations of CD4⁺ Trm cells were a significant component of the immune response in mouse models of lung cancer.

Text

2022-09-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/82771

Microbiology and Immunology

University of British Columbia

UBCV

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