Deciphering the molecular mechanisms through which tumors "manipulate" immune system cells

To decipher the molecular mechanisms through which tumors "manipulate" the cells of the immune system and develop genetic engineering techniques to restore the correct functionality of these cells: these are the objectives of the research of the group led by Dr. Mario Leonardo Squadrito, researcher and Project Leader of the Targeted Cancer Gene Therapy Unit at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET).

Dr. Squadrito's project ''Dissecting microRNA networks in tumor-associated macrophages'' has been among the winners of the Cariplo Foundation call for "Biomedical research conducted by young researchers" 2018. Through this call, the Foundation aims to offer young researchers the opportunity to develop and enhance independent careers by conducting research projects under their own responsibility.

The project is part of research for the treatment of liver metastases, in particular those resulting from colorectal cancer (CRC). Although the primary tumor in this type of carcinoma normally responds well to anticancer therapies, liver metastases remain a rather frequent and very problematic occurrence, since they reduce the treatment options and life expectancy of patients. This is due to the fact that once established in the liver, the tumor "reprograms" the cells of the healthy tissue around it in a pro-tumor sense, pushing them to support their growth and inhibiting the immune response against the tumor itself.

"Our project - says Dr. Squadrito - aims to explore how liver metastases from colorectal cancer "manipulate" the immune system cells present in the liver, such as hepatic macrophages".

In particular, we aim to characterize how the presence of the tumor affects the expression of a particular class of RNA, the microRNAs (miRNAs) which in turn regulate genetic programs within the cell. By restoring the correct expression of miRNAs through genetic engineering techniques, we hope that macrophages could be reprogrammed towards a healthy phenotype [the morphological and functional characteristics of an organism, Ed.] thus restoring the anti-tumor immune response.

Thanks to the Cariplo funding it was possible to form a dynamic research group, where to investigate the molecular mechanisms involved in the reprogramming of the tumor microenvironment. Currently the project involves Dr. Chiara Bresesti as the first author of this line of research. For the group led by Dr. Squadrito, recently formed, winning this grant meant being able to open a new line of research of high scientific interest and, at the same time, with great possibilities for clinical development. This funding will also make it possible to apply cutting-edge molecular techniques such as single-cell RNA sequencing and the use of viral vectors that allow measuring the activity of microRNAs in rare cell populations.