Tumor microenvironment derived biomarkers in renal cell cancer

Abstract

Renal cell carcinoma (RCC) is the 13th most common malignancy worldwide, and constitutes around 2% of all malignant tumors. The entity renal cell carcinoma comprises a heterogenous group of malignant tumors that originates from the epithelial cells in the renal proximal tubule. The most frequently occurring subtype is clear cell renal cell carcinoma which is characterized by a mutation in the von-Hippel-Lindau gene leading to accumulation of hypoxia inducible factor and subsequent upregulation of growth factors involved in angiogenesis. RCC is inherently resistant to conventional chemotherapy, and thus radical surgery before metastasis has occurred still is the best chance for permanent cure. However, in recent years, the introduction of various targeted therapies and immunemodulators have changed the picture, and there are now numerous options which increases the hope for patients with metastatic disease.

In this thesis, we investigated the tumor microenvironment to identify factors with impact on prognosis and response to anti-angiogenic therapy in patients with mRCC. We found that both high perivascular expression of PDGFR-β as well as high heterogeneity of perivascular PDGFR-β was significantly associated with shorter survival. In order to make an in-depth characterization of the tumor microenvironment, we compared vascular, perivascular and stromal features in renal, colorectal and ovarian cancer. This revealed significant differences regarding several metrics, but also similarities. We also studied the impact on tumor infiltrating B-lymphocytes in RCC and found that high infiltration conveyed a worse prognosis, counter to what is seen in many other tumor types, suggesting that high levels B-cells in RCC rather dampens the anti-tumor immune response than indicates an activated immune system. In the last paper, we investigated the role of intratumoral vessel size for response to anti-angiogenic treatment and found that tumors dominated by medium sized vessels was more sensitive to sunitinib.

In summary, our findings indicate that the tumor microenvironment influences prognosis as well as response to treatment in a context dependent manner, and that this prompts further investigation within this field.