Art of tumor immunity: extricating hypoxia-driven immunosuppression in the solid tumor microenvironment

Abstract: The fate of tumors, from initiation to in situ carcinoma and ultimately metastasis, is intricately tied to the balance between the immune system’s effector cytotoxic and tolerogenic immunosuppressive responses, collectively known as tumor immunity. However, this balance is disrupted by hypoxia, a common characteristic of solid tumors, which drives immunosuppression and contributes to the heterogeneity of the solid tumor microenvironment (TME). This thesis aims to uncover and extricate hypoxia-driven immunosuppression in the solid TME by alleviating the suppression on cytotoxic effector cells (Paper I and II) and modulating the myeloid cells into anti-tumor phenotypes (Paper III and IV). With cytotoxic T cells and natural killer (NK) cells being the two main effector cytotoxic cells, Paper I examined how targeting the adenosine (ADO) signaling axis via adenosine-2B receptor (A2BR) restore T cell function and Paper II investigated the influence of pseudohypoxia on NK cells using clear cell renal cell carcinoma (ccRCC) with von HippelLindau (VHL) mutation. The ADO signaling axis via CD39/CD73/extracellular ADO, regulated by hypoxia-inducible factor HIF-1, is upregulated in the hypoxic TME, intensifying the immunosuppressive effects. By targeting the low ADO affinity receptor - A2BR in Paper I, we restored T cell cytotoxicity and pro-inflammatory cytokine production, facilitated infiltration into tumor spheroid, and increased the ratio of CD8 to CD4 T cells. In Paper II, we revealed that VHL mutation in ccRCC creates an immunosuppressive TME characterized by differential protein expressions involved in tumor migration and progression, lower oxygen tension, and upregulation of COX-2 and IL-10. Thereby hindering NK cells, where VHL restoration in ccRCC improved NK cell infiltration and function. These infiltrating NK cells exhibited reduced immune checkpoint expression, lower HIF-1 level, and a more mature phenotype. Within the hypoxic TME of solid tumors, such as pancreatic ductal adenocarcinoma (PDAC), which is the flagship for immunosuppressive cold tumor, monocytes predominantly differentiate into tumor-associated macrophages (TAM) with pro-tumor phenotype. This myeloid cell compartment plays a critical role in shaping the hypoxic and cold TME of PDAC. In Paper III, we identified a specific subset of TAMs expressing formyl peptide receptor-2 (FPR2) in females, which is associated with T cell exhaustion in PDAC. By targeting FPR2, we rescued anti-inflammatory M2 macrophage-mediated T cell suppressive effects, leading to reduced regulatory T cells, improved IFN production and decreased PD-1 and TIM-3 expression in CD8 T cell. In Paper IV, we explored the myeloid cell compartment in PDAC using a 3D spheroid model and a quantitative secretome approach, revealing the complex interplay between hypoxia and the myeloid cell compartment. Inhibiting hypoxia-driven immune checkpoints, endoplasmic reticulum oxidoreductase 1-alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1), modulated the PDAC secretome to upregulate antigen presentation pathways, enhance infiltration and differentiation of dendritic cells (DCs). Taken together, these studies underscore the complexity of tumor immunity and the multifaceted nature of hypoxia-driven immunosuppression. They emphasize that there is no onesize-fits-all approach to relieving immunosuppression, and the context-dependent nature of the solid TME necessitates tailored strategies.

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