Spatial modeling of cytokine-mediated intercellular communication uncovers a potential mechanism behind sex differences in tumor growth

It is known that certain cancers progress differently in men and women. Experiments in mouse bladder cancer, motivated by sex differences in humans, display a sex bias where male tumors grow faster than female tumors. The mechanisms mediating this phenotypic difference on a cellular scale are not yet elucidated. Intercellular communication via the cytokine interferon-gamma (IFNG) has been recognized as a possible contributor to or driver of sex bias due to its abilities to suppress cancer cell proliferation and augment immune cell ability to eliminate cancer cells. It has been shown that this sex bias is dependent on a small subset of cells expressing androgen receptors (AR+ CD8+ T cells) found virtually only in males. Our hypothesis is that sex bias is induced by spatial variations in the IFNG concentration generated by these cells as they sequester IFNG. We investigate whether this can account for sex bias in mice by developing models which simulate the time-evolution of spatial data from mouse tumors. With our simulations, we confirm that this subset of cells can generate the sex bias found in the data. More, our modeling unveils how IFNG communication affects cellular interactions which occur on much longer time scales than that of IFNG diffusion and connects cell behavior at large length scales. Finally, in certain parameter regimes due to cytokine-cell interactions, an emergent moving cytokine front develops which may contribute to the sex bias.