Ontogeny of intestinal intratumoural macrophages and their contribution in cancer regulation

Abstract

Macrophages are tissue-resident myeloid cells that can contribute to the initiation and progression of cancer. A better understanding of their ontogeny and survival mechanisms is crucial for the development of effective macrophage-based immunotherapies. In colorectal cancer, these aspects have not been investigated thus far. In this work, in addition to confirming the monocyte-dependence of F4/80(hi)MHCII(hi) macrophages in colon lamina propria (LP), we have identified a previously overlooked CCR2-independent F4/80(hi)MHCII(lo) macrophage subset, which declines after birth and is almost entirely outcompeted by CCR2-dependent F4/80(hi)MHCII(hi) macrophages. Interestingly, in colon adenomas F4/80(hi)MHCII(lo) cells become the dominant macrophage fraction during tumour progression. In contrast to their LP counterparts, the intratumoural F4/80(hi) macrophages are able to self-renew and lose the bone marrow dependency. Since their depletion via CSF1R blockade diminishes the tumour burden, our data underline the potential of these tumour-promoting intestinal macrophages as an attractive target for successful cancer immunotherapies.