CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression

Abstract

Interleukin 15 (IL-15) regulates the development, survival, and functions of multiple innate and adaptive immune cells and plays a dual role in promoting both tumor cell growth and antitumor immunity. Here, we demonstrated that the in vivo injection of recombinant human IL-15 (200 µg/kg) or murine IL-15 (3 µg/kg) to tumor-bearing NOD-SCID-IL2Rg−/− (NSI) mice resulted in increased tumor progression and CD45+ CD11b+ Gr-1+ CD215+ cell expansion in the tumors and spleen. In B16F10-bearing C57BL/6 mice model, we found that murine IL-15 has antitumoral effect since the activation and expansion of CD8+ T cells with murine IL-15 treatment. But no enhanced or reduced tumor growth was observed in mice when human IL-15 was used. However, both murine and human IL-15 promote CD45+ CD11b+ Gr-1+ CD215+ cells expansion. In xenograft tumor models, CD215+ myeloid cells, but not CD215− cells, responded to human IL-15 stimulation and promoted tumor growth. Furthermore, we found that human IL-15 mediated insulin-like growth factor-1 production in CD215+ myeloid cells and blocking IGF-1 reduced the tumor-promoting effect of IL-15. Finally, we observed that higher IGF-1 expression is an indicator of poor prognosis among lung adenocarcinoma patients. These findings provide evidence that IL-15 may promote tumor cell progression via CD215+ myeloid cells, and IGF-1 may be an important candidate that IL-15 facilitates tumor growth.

IL-15/IL-15Rα Heterodimeric Complex as Cancer Immunotherapy in Murine Breast Cancer Models

“…We have found that the depleting antibody loses its efficacy when IL-15cx is present ( Figure 4 ). This result is consistent with the promotion of CD11b + myeloid cells by IL-15 ( 54 , 55 ). However, in our study IL-15 or IL-15cx treatment has been shown to decrease MDSCs in tumor mice ( Figure 4 ).…”

Crosstalk between IL‐15Rα+tumor‐associated macrophages and breast cancer cells reduces CD8+T cell recruitment

“…These data indicate that there is a novel mechanism capable of converting IL‐15 antitumor signals into tumor‐promoting signals. Similarly, a recent study reported that IL‐15 promoted the proliferation and insulin like growth factor‐1 (IGF‐1) production of IL‐15Rα + myeloid cells (CD45 + CD11b + GR‐1 + ) in lung cancer in immunodeficient mice [ 51 ]. Therefore, whether IL‐15Rα + TAMs exhibit similar functions in tumor types other than breast cancer requires further investigation.…”

Chemokines and Cytokines in Immunotherapy of Melanoma and Other Tumors: From Biomarkers to Therapeutic Targets

“…IL-15 has been described in the pathology of various autoimmune diseases such as rheumatoid arthritis, autoimmune diabetes, inflammatory bowel disease and celiac disease [ 128 ]. In a melanoma mouse model, IL-15 promoted tumor progression by stimulating CD215+ myeloid cells [ 129 ]. In a B16 melanoma model, the upregulation of CCL4 and CCL5 recruited Tregs in a CCR5-dependent manner and promoted tumor progression [ 130 ].…”