Macrophages constitute a major subset of cells in the cancer tumor microenvironment (TME), but despite
decades of research in murine models and in vitro studies on human blood monocyte-derived macrophages
there are no reliable markers to detect the various macrophage functions in the human TME and no systematic
study on human macrophage in vivo functional diversity has been performed. Current understanding of
macrophage biology is based on findings from murine studies and ex vivo experiments on human blood
monocyte-derived macrophages but these have not translated well into human tumor physiology. A
convergence of three novel technologies (Smart-3SEQ, CIBERSORTx and MIBI) now offers an opportunity to
discover novel markers by studying macrophages in vivo at the microscopic level in the actual TME rather than
in a model thereof.
We hypothesize that those studies do not represent the true physiological state in vivo because they lack the
complex context of the human TME. New technologies will enable us to discover subtypes/phenotypes
associated with different functions by directly studying human tumor samples where macrophages are known
to have different activities.
Our proposal represents an entirely novel approach to study TAM by comparing them in the setting of two
distinct carcinomas, breast cancer and colon cancer; two tumor types in which TAM fulfill opposing functions.
We will also analyze TAM at the microscopic level within distinct regions of the TME, thus identifying genes
that distinguish distinct macrophage subsets based on their location within tissue. Finally, we will study
changes in their expression profiles during different stages of tumor progression. This project will provide
fundamental new biological insights into the diversity of macrophages in the context of human cancer. It will
provide new biomarkers that can be used to provide a rational decision for the choice of novel macrophage-