Bi-directional support of T lymphoma and a lymphoma-associated monocyte population involving Notch signaling in mice

Tumor-induced manipulations of myelomonocytic differentiation have been widely reported. Here, we describe the elicitation of a tumor-supportive cell type in a T lymphoma model in mice. We observed that the development of T lymphoma coincided with the appearance of a lymphoma-associated monocytic cell type (LAM) of host origin accompanied by a diminished dendritic cell (DC) population. RNA-sequencing and cytometric analyses revealed that LAMs shared markers with both DCs and with resident macrophages, most closely resembling monocyte-derived DCs (moDCs). The numbers of T lymphoma cells were negatively affected by reducing LAMs suggesting a helper function of LAMs for tumor growth. LAMs expressed Notch ligands, and treatments of lymphoma-carrying mice with Notch signaling-inhibitors LY3039478 and DAPT selectively decreased expansions of T lymphomas with or without Notch1 mutations, respectively. Mature LAMs did not proliferate in the periphery. Instead, their expansion resulted from altered myelomonocytic differentiation in the bone marrows of lymphoma-carrying mice with increases in common monocyte/DC precursors but with reduced granulocyte, monocyte and DC precursor populations. These data suggest that developing T lymphomas are capable of reprogramming monocyte/DC differentiation to increase the numbers of a tumor-promoting DC type, attract it to tumor locations and may engage in Notch ligand-dependent signaling to support lymphoma survival.