Suppression of anti-tumour immunity by the tumour microenvironment remains a major barrier to the development of broadly effective immunotherapies to treat solid tumours. Cytotoxic natural killer (NK) cells are vital to anti-cancer immunity and have shown clinical efficacy for treating hematologic malignancies. However, NK cell therapies have failed to be effective against solid tumours as cytotoxic NK cells become dysfunctional in the tumour microenvironment. While tumours hinder cytotoxic NK cells, they stimulate the tumour-promoting functions of regulatory NK cells. The mechanisms that dictate NK cell polarization and their fate in the tumour microenvironment remain poorly defined but harbour key therapeutic potential. Glucose-driven cellular metabolism has emerged as a central regulator of NK cell anti-tumour activity. Notably, tumour cells have deregulated metabolism, causing a metabolically hostile environment that is low in glucose and oxygen and high in metabolic waste. In the work presented, we demonstrate that NK cells expanded from cancer patients or healthy donors exert strong anti-tumour activity and dismantle the immunosuppressive tumour microenvironments of advanced ovarian and lung cancer. As a result, expanded NK cells were capable of sensitising initially non-responsive patient tumours to PD1 checkpoint-blockade therapy. Further, we uncover that the activity of cellular metabolic pathways plays a key role in NK cell functional fate in tumour microenvironment. We show that the tumour microenvironment induces paralysis of cytotoxic NK cell glucose metabolism to cause their dysfunction. However, reprogramming of NK cell metabolism through expansion arms expanded NK cells with enhanced metabolic flexibility which enabled their anti- tumour activity to be paradoxically strengthened by the tumour microenvironment. We further identify that regulatory NK cells have a distinct metabolic program compared to cytotoxic NK cells, including lower glucose-driven metabolism, that is amenable with the tumour microenvironment. Our work provides new mechanistic insight into how NK cell fate is regulated and how the pathological environment of a tumour capitalizes on this. This knowledge provides new therapeutic targets to intervene with the suppression of cytotoxic immunity in tumours. Further, this work identifies that expanded NK cells are a promising therapeutic candidate that exploit the metabolic hostility of the tumour microenvironment and synergize with other immunotherapies. / Thesis / Candidate in Philosophy / Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy has emerged as a powerful treatment modality. Over the past decade, immune cell therapies have revolutionized the treatment of blood cancers like leukemia and lymphoma. Yet despite the potential, immune cell therapies have failed to be broadly effective against solid tumours because the anti-cancer activity of immune cells, such as Natural Killer (NK) cells, becomes severely impaired by the tumour environment. In this work, we identify that NK cells expanded from cancer patients and healthy donors overcome suppression by tumours and eliminate detectable tumour in pre-clinical models of advanced ovarian and lung cancer. These expanded NK cells also enhanced the functions of other immunotherapies. Further, we shed new light on how NK cells become dysfunctional in tumours. We uncover that NK cells undergo a metabolic energy crisis in tumours that causes their dysfunction, but that expanded NK cells have increased metabolic fitness which allows them to overcome this energy crisis and remain highly functional. Finally, we also characterize the metabolism of a subset of NK cells that are tumour-promoting and find that they harbour metabolic advantages to thrive in tumours. Overall, our work provides new insight as to how to overcome immunosuppression by tumours. This work identifies that expanded NK cells are a promising therapeutic candidate that exploit the hostility of tumours and synergize with other immunotherapies.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/28811 |
| Date | January 2023 |
| Creators | Poznanski, Sophie M. |
| Contributors | Ashkar, Ali, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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