FIGURE 2.

Effect of H₄ receptor activation in tumor cells and the tumor microenvironment (TME). Histamine or selective H₄ receptor agonists play important roles at a variety of stages during tumor development and in multiple cell types including cancer and immune cells. On the one hand, H₄ receptor activation exerts a direct in vitro cytotoxic effect on TNBC cells, whereas on the other the H₄ receptor selectively affects the distribution of different immune cell populations in the TME, modulating the local and systemic immune responses. In a TNBC murine model, H₄ receptor stimulation increases the percentage of CD4⁺ tumor‐infiltrating T cells, whereas it decreases the infiltration of NK cells and CD19⁺ B lymphocytes. In addition, it increases IL‐10 secretion levels, whereas decreases IFNγ levels in tumor‐conditioned medium from wild‐type (WT) mice. Likewise, tumor draining lymph nodes (TDLN) of WT mice show higher proportions of CD4⁺ T cells and T regulatory cells (CD4⁺ CD25⁺ FoxP3⁺), a reduced percentage of NK cells, and decreased TNFα levels in TDLN compared with H₄ receptor‐KO mice, thus suggesting an immunosuppressive effect of H₄ receptor¹¹⁴, ¹⁴⁹