Boosting of tumor cell killing by cytotoxic lymphocytes may be a promising means to enhance anti-tumor immunity. Prior studies demonstrated that tumor infiltration by cytotoxic lymphocytes correlates with control of tumor growth and is associated with an improved prognosis in cancer patients. Trafficking of activated lymphocytes is a tightly regulated mechanism and the specific nature of the chemokine milieu is a crucial determinant for permitting T cell entry into the tumor microenvironment. CXCL10 is an interferon-inducible chemokine particularly important for the recruitment of activated T, and it has been shown to enhance anti-tumor responses through its action on cytotoxic T cells (e.g., glioblastoma, colorectal adenocarcinoma and lung carcinoma). Additionally, roles for CXCL10 as an anti-tumor effector include its ability to chemo-attract NK cells into sites of inflammation, and its ability to inhibit development of new vasculature and induce the regression of newly formed vessels. Adding a layer of complexity, the function of CXCL10 can be regulated by dipeptidylpeptidase IV (DPPIV), leading to the formation of a dominant negative, antagonist form of the chemokine. This was initially demonstrated in vitro, and recent work has provided convincing in vivo evidence that antagonist forms of CXCL10 regulate lymphocyte trafficking. The main goal of this protocol is to evaluate the tolerance of sitagliptin treatment in HCC patients, and secondary DPPIV inhibitors as a strategy for protecting CXCL10 chemokine agonist activity as a means to enhance tumor regression.

The study will be conducted in 15 patients. Patient selection will be made based on medical records during a weekly staff meeting. After collection of informed consent, the patients will undergo a biopsy of the tumor and of the not-tumoral liver and 2-4 weeks later HCC resection.

The study will include a phase of 3 weeks [± 7 days] administration of sitagliptin as monotherapy (taken orally) after liver biopsy and before HCC resection. The window of ± 7 days is deliberately wide to take in account the variable arrangements made for surgical resection. Nevertheless we will make our efforts to focus on a three weeks regimen. Three doses of sitagliptin will be used: 1) 100mg/day (dose recommended in the SmCP), 2) 200mg/day and 3) 600mg/day; with 5 patients in each group. Arrangements will be made for surgical resection upon standard care. Blood samples will be obtained for immunology studies at each visit. The study will end one week after surgery (or less if the state of health of the patient does not require to stay longer in the hospital). Patients will continue their treatment for HCC as prescribed by the clinician.

Inclusion Criteria:

• Patients with 18 years old the day of inclusion.
• For women, a negative blood pregnancy test before inclusion is necessary. Note: this test will be done only to women of childbearing age and non menopausal.
• HCC based on medical imaging with indication of liver resection and without contra-indication of preoperative liver biopsy.
• Minor resection not exceeding 2 liver segments
• No cirrhosis or cirrhosis with a Child-Pugh Score Class A. Note: this score is used worldwide to assess liver function in cirrhosis.
• Informed consent must be obtained for all subjects prior to study entry.
• Patients affiliated to health policy insurance.

Exclusion Criteria:

• Presence of HIV Infection.
• Presence of renal impairment (CrCl <60 ml / min).
• Liver function compromised (Child Pugh B, MELD score > 9)
• Indirect sign of portal hypertension (Oesophagal Varices, splenomegaly, platelet count less than 100.000)
• A need for major hepatic resection (more than 2 segments)
• Taking digoxin (digitalis) within 6 months of starting treatment.
• History of severe hypersensitivity reaction (such as anaphylactic shock or angioedema) to sitagliptin.
• Patients with diabetes.
• Pregnant or absence of an effective contraception for women.
• A person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure.
• Living conditions suggesting an inability to track all scheduled visits by the protocol.
• Life expectancy less than 3 months.