Panoply™ Human TNFSF15 Over-expressing Stable Cell Line

Unlike M1-type macrophages, which possess anti-cancer properties, M2-type macrophages in malignant tumors significantly promote tumor progression and metastasis. Consequently, increasing the M1/M2 ratio is a promising strategy for improving the tumor immune microenvironment to suppress cancer. Here, researchers discovered that TNFSF15 (tumor necrosis factor superfamily member 15), a cytokine with anti-angiogenic activity, promotes the differentiation and polarization of macrophages toward the M1 phenotype. Experiments demonstrated that tumor growth was inhibited in mice injected with Lewis lung carcinoma (LLC) cells engineered to overexpress TNFSF15; these tumors exhibited a higher proportion of M1-type macrophages compared to those formed by control-transfected LLC cells. Treatment of the murine macrophage cell line RAW264.7 with recombinant TNFSF15 enhanced their phagocytic and pro-apoptotic capabilities against cancer cells. Mechanistic studies revealed that TNFSF15 activates STAT1/3 signaling pathways in myeloid cells, as well as MAPK, Akt, and STAT1/3 pathways in undifferentiated macrophages; furthermore, in M2-type macrophages, TNFSF15 activates the STAT1/3 pathway while inhibiting the STAT6 pathway. The modulation of these signaling pathways drives the macrophage phenotype shift toward the M1 type. The ability of TNFSF15 to promote macrophage differentiation and polarization toward the M1 phenotype suggests that this unique cytokine holds potential value for remodeling the immune microenvironment to favor tumor suppression.

Bone marrow-derived macrophages constitute a significant component of tumor-associated macrophages (TAMs). To investigate whether bone marrow cells participate in TNFSF15-mediated intratumoral M1 macrophage accumulation, researchers analyzed bone marrow cell populations in mice bearing TNFSF15-overexpressing LLC tumors. The results showed that elevated intratumoral TNFSF15 levels led to a significant reduction in the populations of HSCs (Lin−c-Kit+Sca-1+ hematopoietic stem cells), GMPs (granulocyte-monocyte progenitors), and CD115+CD11b+ precursor cells in the bone marrow (Figure 1A). Furthermore, researchers inoculated mice possessing red fluorescent (tdTomato+) bone marrow cells with LLC tumors and injected recombinant TNFSF15 into the peritumoral region. Notably, compared to control tumors, TNFSF15-treated tumors exhibited a nearly twofold increase in the infiltration of tdTomato+ macrophages (Figure 1B), indicating that TNFSF15 promotes the differentiation of bone marrow-derived macrophages and their mobilization to the tumor site.

Figure 1. TNFSF15 promotes the differentiation of bone marrow cell into M1 macrophage. (Zhao C C, et al., 2022)