Identification of genetic loci that control mammary tumor susceptibility through the host microenvironment

The interplay between host genetics, tumor microenvironment and environmental exposure in cancer susceptibility remains poorly understood. Here we assessed the genetic control of stromal mediation of mammary tumor susceptibility to low dose ionizing radiation (LDIR) using backcrossed F1 into BALB/c (F1Bx) between cancer susceptible (BALB/c) and resistant (SPRET/EiJ) mouse strains. Tumor formation was evaluated after transplantation of non-irradiated Trp53-/- BALB/c mammary gland fragments into cleared fat pads of F1Bx hosts. Genome-wide linkage analysis revealed 2 genetic loci that constitute the baseline susceptibility via host microenvironment. However, once challenged with LDIR, we discovered 13 additional loci that were enriched for genes involved in cytokines, including TGFβ1 signaling. Surprisingly, LDIR-treated F1Bx cohort significantly reduced incidence of mammary tumors from Trp53-/- fragments as well as prolonged tumor latency, compared to sham-treated controls. We demonstrated further that plasma levels of specific cytokines were significantly correlated with tumor latency. Using an ex vivo 3-D assay, we confirmed TGFβ1 as a strong candidate for reduced mammary invasion in SPRET/EiJ, which could explain resistance of this strain to mammary cancer risk following LDIR. Our results open possible new avenues to understand mechanisms of genes operating via the stroma that affect cancer risk from external environmental exposures

Phenotypic characteristics of commonly used inbred mouse strains

202103 bcvcAccepted ManuscriptRGC1-ZVN0Publishe

Myeloid-Derived Suppressor Cells in Tumor-Induced T Cell Suppression and Tolerance

Tumor development is often associated with a deep alteration of normal myelopoiesis, leading to a progressive accumulation of various cellular elements, belonging to myelomonocytic lineage, in the tumor bed, in the blood, and in both primary and secondary lymphoid organs. This heterogeneous pool of cells expresses, in the mouse, the common markers CD11b and Gr-1 (Ly6C/G) and is endowed with the ability to suppress antigen and/or polyclonal-driven T cell immune response. These cells, named myeloid-derived suppressor cells (MDSCs), are mobilized from hematopoietic organs by cytokines and other factors produced by the tumors, as well as by strong activation of the immune system, and have a profound influence on the outcome of the T cell-dependent immune responses. MDSCs can restrain T cell function directly in an antigen-independent manner; however, in vivo, MDSCs can also process and present tumor-associated antigen and can lead to T cell tolerance in an antigen-specific manner. Furthermore, MDSCs seem to be key players in tumor-induced suppressive network that includes T regulatory (Treg) cells, inhibitory natural killer T (NKT) cells, mast cells, Th17, as well as effector T cells. The importance of MDSCs in human malignancies has been demonstrated in recent years and new approaches targeting their suppressive/tolerogenic action are currently being tested in both preclinical model and clinical trials