Immunotherapy represents a promising approach for cancer treatment but is frequently ineffective due to immune escape mechanisms or ineffective tumor leukocyte infiltration. To further extent the remarkable success of tumor immunotherapy, a better understanding of the mechanisms that regulate immune cell recruitment and function in the tumor microenvironment is required. Metastatic colorectal cancer (CRC) is one of the main causes of death associated with tumors. Myeloid cells play an important role in CRC carcinogenesis and progression due to release of factors that promote tumor growth and suppress the immune response. Indeed, elmination of myeloid cells, or blockade of their tissue recruitment reduce tumor incidence and the ability to form liver metastases in CRC mouse models. Accumulating evidence suggests that myeloid cells inhibit NK cell anti-tumor activity, thus limiting cancer immune surveillance. Correspondingly, we found that CRC liver metastasis are associated with the expansion of lymphoid cells resembling a recentlly described NK cell-derived population of intILC1 with pro-tumoral function.
The chemokine system has a central role in orchestrating the immune response in tumor determining extravasation to primary tumor and to metastatic sites and activation of anti-tumor potential. The main objective of the present proposal is to improve the anti-tumor immune response by inhibiton of myeloid cell tumor infiltration in combination with strategies that promote of NK cell-mediated effector functions. Thus we will i) identify myeloid cell populations with NK/ILC1 suppressive activity that expand in CRC liver metastasis ii) inhibit their tissue recruitment by chemokine receptor targeting; iii) clarify the molecular basis and effects of innate lymphoid cell plasticity and mechanisms of recruitment in CRC metastasis; iv) identify new potential strategies of immunotherapies, by manipulation of the chemokine system to unleash the anti-tumor activity of NK/ILC1.
