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.
Quantification of the immune and inflammatory landscape of TME has provided novel prognostic indicators of cancer progression as shown by quantification of tumor infiltrating T cells and TAM. Genomic technologies have added a new dimension to the characterization of the TME and to classification of cancers. Finally, dissection of the impact of IC inhibitors and adoptive cell therapy of hematological malignancies have proven the principle that the immune system can be harnessed to cope with advanced disseminated neoplastic diseases.
Response to IC inhibition is restricted to a small fraction of patients with metastatic CRC and approaches to increase tumor immunogenicity and infiltration by immune cells are urgently needed. Thus, identification of mechanisms of NK/ILC1 accumulation and activation in metastatic liver, as well as the understanding of NK/ILC1 susceptibility to IC-mediated suppression will help to design new combinatorial therapeutic strategies.
The identification of novel cellular and molecular pathways involved in regulation of the inflammatory response mediated by ILC in liver during metastatic dissemination will have profound implications in the Public Health at several levels: 1) correlations between ILC transcriptional states/phenotypes and cancer metastasis will improve the prognostic power of the Immunoscore, recently proposed for CRC; 2) the transcriptomic data we plan to generate in this proposal will have the potential to reveal new biological pathways and players involved in NK/ILC function during liver metastasis formation, which can be used as biomarkers to predict metastasis and to generate novel therapeutic strategies; 3) mechanistic studies will pave the way to design novel NK/ ILC-based cellular therapies of CRC.
The recent use of approaches to target chemokine receptor/ligand axes acting on selected cell lineages is proving effective in shaping the immune infiltrate in diseases, thus allowing to control unwanted immune responses. Thus, CCR2/CCL2 inhibition is currently being tested in clinical trials to reduce TAM and improve efficacy of conventional therapy in metastatic tumors such as pancreatic cancer. Furthermore, approaches to re-activate pro-inflammatory chemokine expression, often silenced in tumors, are emerging as fundamental to enhance or even allow efficacy of current immunotherapy in solid tumors (Chow et al. Immuity 2019, Dangaj et al., Cancer cell 2019).