Antitumor Activity of TLR7 Is Potentiated by CD200R Antibody Leading to Changes in the Tumor Microenvironment

Abstract

Stimulation of Toll-like receptor 7 (TLR7) activates myeloid cells and boosts the immune response. Previously, we have shown that stimulation of the inhibitory CD200 receptor (CD200R) suppresses TLR7 signaling and that the absence of CD200R signaling leads to a decreased number of papillomas in mice. Here, we investigated the effects of agonistic anti-CD200R on the antitumor activity of a TLR7 agonist (R848) in a syngeneic mouse tumor model. Intratumoral administration of R848 inhibited the growth of the CT26 colon carcinoma and simultaneously decreased CD200R expression in tumor-infiltrating immune cells. The antitumor effects of R848 were potentiated by anti-CD200R. Successfully treated mice were resistant to rechallenge with the same tumor cells. However, the immediate antitumor effects were independent of lymphocytes, because treatment efficacy was similar in wild-type and mice. Administration of R848, particularly in combination with anti-CD200R, changed the phenotype of intratumoral myeloid cells. The infiltration with immature MHC-II macrophages decreased and in parallel monocytes and immature MHC-II macrophages increased. Combined treatment decreased the expression of the macrophage markers F4/80, CD206, CD86, CD115, and the ability to produce IL1β, suggesting a shift in the composition of intratumor myeloid cells. Adoptively transferred CD11b myeloid cells, isolated from the tumors of mice treated with R848 and anti-CD200R, inhibited tumor outgrowth in recipient mice. We conclude that administration of agonistic anti-CD200R improves the antitumor effects of TLR7 signaling and changes the local tumor microenvironment, which becomes less supportive of tumor progression. .

The pro-tumor effect of CD200 expression is not mimicked by agonistic CD200R antibodies

“…In this study, using several additional tumor models with various degree of intratumoral inflammation, we confirmed that anti-CD200R mono treatment does not have therapeutic effect without additional inflammation. In contrast, using a model of colon carcinoma we have recently shown that anti-CD200R treatment suppresses tumor growth and modifies immune cell recruitment but only in the presence of TLR7-induced inflammation [27].…”

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“…Furthermore, it should be taken into account that macrophages contribute to antitumor reactions 14. It has been shown preclinically that macrophage proliferation in tumors is repressed, and TAM half-lives are shortened in comparison to resident macrophages of corresponding normal tissues 15,16. As a result, aggregation of TAMs in the tumor microenvironment, particularly M1 TAMs with phagocytic capability, is indispensable to TAM quantity protection and antitumor immunity in human cancers 17,18.…”

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“…Previous studies have shown that the intratumoral administration of R848 inhibits tumor growth and decreases CD200R expression on tumor-infiltrating immune cells in a syngeneic CT26 colon carcinoma mouse model. These results indicate that the antitumor activity of the TLR-7/TLR-8 agonist (R848) is mainly driven by an anti-CD200R effect causing changes in the tumor microenvironment (TME) (32).…”

“…Over many years, the potent stimulatory effects of Toll-like receptors (TLRs) on the immune system have urged efforts aiming to develop immune vaccines that use TLR agonists as immunological adjuvants ( 31 , 32 ). Motolimod (VTX-2337) and resiquimod (R848) are TLR-8 and TLR-7/TLR-8 agonists respectively, that deliver adjuvant-like signals to APCs.…”