Messaoudi, Nouredin

Abstract: Colorectal cancer (CRC) constitutes the third most frequent type of cancer worldwide. Approximately 50% of all patients with CRC develop liver metastases (CRLMs) in the course of their disease. Liver resection in combination with systemic chemotherapy is regarded as the most effective and potentially curative treatment strategy for CRLMs, with a 5-year survival rate surpassing 50%. Despite the advent of modern chemotherapy and broadened surgical indications for liver resection, the majority of patients develop recurrent disease within 2 years after hepatectomy. Although current risk assessment tools based on clinicopathological factors have been generally informative, they have however failed to incorporate the prognostic relevance of immune evasion as an important hallmark of cancer growth and progression. Moreover, immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic CRC. New targeting immunosuppressive metabolic pathways are therefore being explored as a novel immunotherapeutic approach. As such, the CD73-adenosine axis represents a promising target in immuno-oncology. Extracellular adenosine is a potent immunosuppressive metabolite of ATP released by cancer and immune cells in the tumor microenvironment. The membrane-bound and soluble homodimer nucleotidase CD73 is the rate-limiting enzyme in the ATP to adenosine degradation pathway. CD73 is also an adhesive and signaling molecule that has been associated with cancer proliferation, invasion, metastasis, neovascularization and drug resistance. In this thesis, we focus on the prognostic value of CD73 expression in CRLMs, claiming that high intratumoral CD73 levels, measured by immunofluorescence, may be useful in predicting a subgroup of patients with poor pathological features, shorter recurrence time and worse survival, independently from other clinico-pathological variables. This groundwork defines the biological relevance and potential rationale of targeting CD73 in now-designed clinical immune-oncology trials using blocking antibodies or inhibiting the adenosine A2A receptor in patients with CRLMs. While histopathology and immune scoring of primary CRC are well studied, comparatively little is known about metastatic CRC lesions. We therefore address in this thesis associations between histopathological growth patterns (HGPs) of CRLMs and three adaptive immune features, representing effector T cells (CD3), antigen presentation (MHC-I), and immunosuppression within the tumor microenvironment (CD73). After validating the prognostic value of HGPs, our main contribution is to find that CD73 expression was the immune marker best able to further stratify patients. This thesis advocates however that no single biomarker can accurately predict outcome, but that models integrating clinical, histological, immune and other parameters are needed to guide clinical decision making in CRLM patients

Immunosuppressive impact of the CD73-adenosine pathway in colorectal cancer liver metastasis : a paradigm shift towards immune-based prognostication

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