Hipoksinin Anti-Tümor İmmün Yanıt Üzerine Etkisinin Araştırılması

Abstract

Inhibition of tumor angiogenesis has been extensively utilized in the treatment of metastatic colorectal cancer and renal cell carcinoma. Complete disruption of tumor angiogenesis results in hypoxia which promotes tumor metastasis and treatment resistance. Although angiogenesis inhibitors are successful to some extent, majority of patients experience the recurrence and acquired resistance. Spatial and temporal changes in tumor microenvironment sculpt the anti-tumor immune response. However, little is known how tumor oxygenation and vessel normalization in vivo influence immune infiltration in YUMMER melanoma tumors. We hypothesized that tumor vessel structure implicates in immune cell composition in melanoma. Therefore, we utilized a previously well-defined mouse model which targets one copy of Phd2 gene. Haplodeficiency of Phd2 normalizes the endothelial alignment and improves pericyte coverage of blood vessels, thereby increasing tumor perfusion and oxygenation. We demonstrated that mitigation of “true” hypoxia through blood vessel normalization improves anti-tumor immunity, thereby delaying tumor growth. In addition, our study highlighted that disruption of hypoxia using Phd2 haplodeficient mouse model re-shaped tumor microenvironment through improved CD4+ and CD8+ T cell infiltration, recruitment of pro-inflammatory macrophages, and diminished infiltration of PD-L1hi anti-inflammatory macrophages. Subsequently, tumor growth is delayed in a T cell dependent manner. In conclusion, Phd2 haplodeficiency restores tumor oxygenation and enhances anti-tumor immune cell infiltration in melanoma tumors.