Serum‐derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor

Altered interaction between CD 200 and CD 200R represents an example of “checkpoint blockade” disrupting an effective, tumor‐directed, host response in murine breast cancer cells. In CD 200R1 KO mice, long‐term cure of EMT 6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB /c mice. The reverse was observed with 4 THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD 200R1 KO . We explored possible explanations for this difference. We measured the frequency of circulating tumor cells ( CTC s) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells ( CTC s) in peripheral blood was equivalent in the two models in WT and CD 200R1 KO mice. Increased metastasis in EMT 6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum‐derived exosomes, from 4 THM tumor bearers, an effect which was attenuated by anti‐ IL ‐6, and anti‐ IL ‐17, but not anti‐ TNF α , antibody. Anti‐ IL ‐6 also attenuated enhanced migration of EMT 6 cells in vitro induced by 4 THM serum or exosomes, or recombinant IL ‐6. Exosome cytokine proteomic profiles responses in 4 THM and EMT 6 tumor‐bearing mice were regulated by CD 200: CD 200R interactions, with attenuation of both IL ‐6 and IL ‐17 in 4 THM CD 200 tg mice, and enhanced levels in 4 THM CD 200R1 KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential.