ILDR2 impairs antitumor surveillance by recruiting immunosuppressive CCR2⁺ monocytes

B7 family co-inhibitory molecules play a crucial role in maintaining homeostasis and preventing chronic inflammation. However, they also impede antitumor immune responses. Immunoglobulin-like domain-containing receptor 2 (ILDR2) is a B7 family member that modulates T cell activation. Previous studies demonstrated that its blockade synergizes with PD-L1 inhibition in mouse tumor models. Although ILDR2 likely contributes to immune evasion, the precise underlying mechanism remains unknown. Here, we investigated the effect of ILDR2 on the tumor microenvironment (TME) in a mouse squamous cell carcinoma (SCCVII) model. We generated ILDR2-expressing SCCVII cells (ILDR2-SCCVII) through transduction of the extracellular and transmembrane domains of ILDR2. Compared to control vector-transduced cells (Cont-SCCVII), ILDR2-SCCVII cells resulted in accelerated tumor growth and a reduced ratio of activated T cells in the TME 21 days after inoculation. At this late stage, most tumor-infiltrating leukocytes were Ly6C- F4/80⁺ CD206⁺ M2-like macrophages. Interestingly, at an earlier time point, we observed the increased infiltration of Ly6C⁺ F4/80^-/⁺ monocytes-potential macrophage precursors-in ILDR2-SCCVII tumors. Whereas CCL2 expression was enhanced early after inoculation in both groups, its receptor CCR2 was more highly expressed on Ly6C⁺ F4/80^-/⁺ monocytes specifically in the ILDR2-SCCVII group. Using our in-house anti-mILDR2 monoclonal antibody and ILDR2-Ig, we found that early recruited myeloid cells preferentially expressed ILDR2 and exhibited ILDR2-Ig binding. These results suggest that tumor-expressing ILDR2 interacts with myeloid cells during the early stages of tumor development, inducing premature monocyte accumulation via the CCL2-CCR2 axis. This early shift toward an M2 macrophage-mediated immunosuppressive environment likely accelerates tumor growth.