| Shrnutí: | <p>Ovarian cancer is notoriously lethal, killing almost 60% of women within 5 years of their diagnosis. Despite advances in survival for many other cancers through the introduction of immunotherapy, the mainstay of ovarian cancer treatment remains chemotherapy. Clinical trials of immunotherapy agents have proven resolutely unsuccessful in ovarian cancer, a finding that has challenged scientists and clinicians over the last decade. Specifically, how does ovarian cancer exist in a context in which it continues to grow and metastasise without recognition by the innate or adaptive immune system? Improving our understanding of this axis will require a closer exploration of the relationship between ovarian cancer cells and the immune cells within their microenvironment. </p>
<p>In this thesis, we explore this relationship through the perspective of the oncogenic RNA-binding protein LARP1, based on our finding that LARP1 is present both in cancer cells and in immunosuppressive macrophages from the earliest stages of ovarian cancer formation. Macrophages are crucial regulators of the tumour microenvironment, and their polarisation state determines whether they accept or reject cancer cells. We show, for the first time, that tumour LARP1 is responsible for reprogramming macrophages to support and perpetuate tumour growth. We find that LARP1 is crucial for anti-inflammatory macrophage polarisation and show that this is enabled by LARP1-dependent metabolic activity. Tumour LARP1 expression promotes anti-inflammatory polarisation in macrophages in the vicinity, and LARP1 expression itself is upregulated in macrophages by proximity to tumour cells. LARP1 is therefore implicated in two ways in anti-inflammatory tumour-associated macrophage phenotype: intrinsically within the macrophages, and by influencing secreted factors from the tumour cells. </p>
<p>In this work, we introduce new roles for LARP1 in the tumour microenvironment and implicate it in ovarian tumour-immune system crosstalk. Our findings pose important questions about how this axis can be interrupted and what additional factors must work alongside LARP1 to maintain this immunosuppressive environment. </p>
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