Natural Killer cells and immunotherapy in colorectal cancer: the evaluation of a patients’ cohort enrolled at Galliera Hospital in Genova

NKK Project is a no-profit study born from the collaboration between the Molecular Immunology Laboratory of the DIMES of the University of Genoa and the Galliera Hospital. Patients affected by colorectal cancer (CRC) candidate for surgery were enrolled to evaluate possible correlations between the phenotypic pattern of Natural Killer (NK) cells derived from patients and their clinical follow-up, to identify new biomarkers of response to immunotherapy (IT) for selecting patients who could mostly benefit from it and to find the rationale to hypothesize new combinations of Immune Checkpoint Inhibitors (ICIs) to better exploit the anti-tumor effect of NK cells. NK cells can recognize and destroy tumor cells lacking HLA-molecules, which for this reason are invisible to T cells. NK cells’ activity is given by the balance between activating and inhibitory receptors expressed on their surface which interact with ligands expressed on tumor cells. For example, the binding of PD-1 to PD-L1/L2 inhibits NK cell functions. CRC is the third most common solid tumor in the world and the second cancer for mortality. It appears in 70% of cases as confined disease, but it develops metastases in 20-50% of them. In our cohort of patients, stage II was the most frequent, followed by stage III and IV. Microsatellites status was tested in 77 out of 83 CRC patients: about 23% of them showed microsatellite instability (MSI). MSI condition is associated with better prognosis in early stages, moreover it is able to predict the efficacy of IT for CRC, and to indicate the use of Pembrolizumab in metastatic disease. Four of our MSI patients were treated with Pembrolizumab. Instrumental evaluation of response to treatment, and also the diagnosis of the onset of immune-related toxicities was carried out using CT scans and PET. Many elements have been explored so far and some of them are used in clinical practice, such as dMMR status, PD-L1 expression and the tumor mutational burden. Besides, other factors such as the role of the tumor microenvironment and HLA-I expression are still under study and need more in-depth investigations. Our data suggest that a possible correlation between the phenotypic pattern of immune and tumor cells could help to identify patients who could most benefit from IT, also combining different ICIs and anticipating immunotherapy in earlier stages of disease.