B7 family co-inhibitory molecules help maintain immune homeostasis and prevent chronic inflammation but can also limit effective antitumor immunity. Immunoglobulin-like domain-containing receptor 2 (ILDR2) is a B7 family member reported to modulate T cell activation. Previous preclinical work indicated that blocking ILDR2 can synergize with PD-L1 inhibition in mouse tumor models, implicating ILDR2 in tumor immune evasion. The exact cellular and molecular mechanisms through which ILDR2 alters the tumor microenvironment (TME) were not previously defined.
To investigate ILDR2’s role in the TME, the authors used a murine squamous cell carcinoma line (SCCVII). They generated ILDR2-expressing SCCVII cells (ILDR2-SCCVII) by transducing the extracellular and transmembrane domains of ILDR2 into the tumor cell line. These were compared with vector-transduced control cells (Cont-SCCVII) following inoculation into mice. The experimental system therefore examines the effect of tumor-cell surface expression of ILDR2 on immune cell recruitment, activation, and downstream tumor growth dynamics.
Tumors formed from ILDR2-SCCVII cells exhibited accelerated growth relative to controls. By 21 days after inoculation, the TME of ILDR2-expressing tumors showed a reduced ratio of activated T cells compared with Cont-SCCVII tumors, indicating impaired antitumor T cell responses at this later stage. The reported observations link tumor expression of ILDR2 with diminished T cell activation within the tumor lesion at the measured late time point.
Analysis of tumor-infiltrating leukocytes revealed distinct temporal kinetics. At the earlier time point assessed (not specified in the abstract), ILDR2-SCCVII tumors had increased infiltration of Ly6C+ F4/80-/+ monocytes, a population consistent with circulating or newly recruited monocytes that can serve as precursors for tumor macrophages. By the later time point (day 21), the majority of tumor-infiltrating leukocytes were Ly6C- F4/80+ CD206+ M2-like macrophages, a phenotype associated with immunosuppressive, pro-tumor macrophage polarization. These findings indicate a shift in myeloid composition from recruited monocytes to M2-polarized macrophages during tumor progression in the presence of tumor ILDR2.
The chemokine CCL2 and its receptor CCR2 are known regulators of monocyte recruitment. In this model, tumor CCL2 expression increased early after inoculation in both ILDR2-SCCVII and control tumors. However, CCR2 expression was higher on Ly6C+ F4/80-/+ monocytes specifically in ILDR2-expressing tumors. The authors also report that early recruited myeloid cells preferentially expressed ILDR2 and showed binding to ILDR2-Ig in assays using an in-house anti-mILDR2 monoclonal antibody and ILDR2-Ig. Together, these data support a model in which tumor-expressed ILDR2 interacts with recruited myeloid cells and promotes accumulation of CCR2+ monocytes via the CCL2–CCR2 axis.
Based on the observed temporal changes, the authors propose that tumor expression of ILDR2 facilitates early accumulation of CCR2+ monocytes. These monocytes then appear to give rise to an increased population of M2-like macrophages (Ly6C- F4/80+ CD206+) at later stages. The resultant M2-dominant myeloid compartment in the TME correlates with fewer activated T cells and faster tumor growth. In summary, tumor ILDR2 may drive a premature shift toward an immunosuppressive, macrophage-mediated microenvironment that impairs antitumor surveillance.
The investigators used an in-house anti-mILDR2 monoclonal antibody and an ILDR2-Ig fusion reagent to probe ILDR2 expression and binding. Using these tools, they found that early recruited myeloid cells preferentially expressed ILDR2 and bound ILDR2-Ig, consistent with direct engagement between tumor ILDR2 and myeloid cell populations during early tumor development.
These findings identify ILDR2 as a tumor-expressed regulator of myeloid recruitment and polarization in a mouse squamous cell carcinoma model, implicating the CCL2–CCR2 axis and subsequent M2 macrophage accumulation in ILDR2-driven immune suppression. This mechanistic insight helps explain prior observations that ILDR2 blockade can cooperate with PD-L1 inhibition to enhance antitumor responses in mice.
Limitations and details not reported in the PubMed abstract: the abstract does not provide full experimental parameters (exact early time point(s) analyzed, quantitative measures of cell fractions, sample sizes, statistical analyses, or other methodological specifics). Those details and complete data are available in the full text of the cited Biochemical and Biophysical Research Communications article.
In the SCCVII mouse model, tumor expression of ILDR2 is associated with early recruitment of CCR2+ monocytes, preferential ILDR2 expression on early myeloid cells, later accumulation of M2-like macrophages, reduced activated T cells in the TME by day 21, and accelerated tumor growth. The authors propose that ILDR2 promotes immune evasion by engaging the CCL2–CCR2 axis to shift the myeloid compartment toward an immunosuppressive phenotype.