Intraoperative Resection Guidance with Photoacoustic and Fluorescence Molecular Imaging Using an Anti-B7-H3 Antibody-Indocyanine Green Dual Contrast Agent.

Purpose: Breast cancer often requires surgical treatment including breast-conserving surgical resection. However, with current postsurgical histologic margin analysis, one quarter of breast cancer patients undergo reexcision to achieve negative margins corresponding to decreased local recurrence and better outcomes. Therefore, a method with high resolution and specificity for intraoperative margin assessment is needed.Experimental Design: First, quantitative immunofluorescence staining of B7-H3 expression was assessed in four pathologic stages of breast cancer progression of the MMTV-PyMT transgenic murine model. Next, an antibody-dye contrast agent, B7-H3-ICG, was injected into mice prior to surgical resection of breast cancer. Anatomic ultrasound, spectroscopic photoacoustic (sPA), and fluorescence imaging were used to guide resection of mammary glands suspected of containing cancer. Resected tissues were processed for H&E staining and pathologic assessment and compared with sPA and fluorescence imaging signals.Results: Tissue containing DCIS (46.0 ± 4.8 a.u.) or invasive carcinoma (91.7 ± 21.4 a.u.) showed significantly higher (P < 0.05) B7-H3 expression than normal and hyperplastic tissues (1.3 ± 0.8 a.u.). During image-guided surgical resection, tissue pieces assessed as normal or hyperplastic (n = 17) showed lower average sPA (3.17 ± 0.48 a.u.) and fluorescence signal [6.83E07 ± 2.00E06 (p/s)/(µW/cm²)] than DCIS and invasive carcinoma tissue (n = 63) with an average sPA signal of 23.98 ± 4.88 a.u. and an average fluorescence signal of 7.56E07 ± 1.44E06 (p/s)/(µW/cm²) with AUCs of 0.93 [95% confidence interval (CI), 0.87-0.99] and 0.71 (95% CI, 0.57-0.85), respectively.Conclusions: It was demonstrated that sPA and fluorescence molecular imaging combined with B7-H3-ICG agent can assess the disease status of tissues with high diagnostic accuracy, intraoperatively, with high resolution, sensitivity, and specificity. Clin Cancer Res; 24(15); 3572-82. ©2018 AACR.

B7-H3 participates in the development of experimental pneumococcal meningitis by augmentation of the inflammatory response via a TLR2-dependent mechanism.

In addition to a well-documented role in regulating T cell-mediated immune responses, B7-H3, a newly discovered member of the B7 superfamily, has been recently identified as a costimulator in the innate immunity-mediated inflammatory response. In this study, we further report that B7-H3 participates in the development of pneumococcal meningitis in a murine model. Exogenous administration of B7-H3 strongly amplified the inflammatory response, exacerbated blood-brain barrier disruption, and aggravated the clinical disease status in Streptococcus pneumoniae-infected C3H/HeN wild-type mice. Consistent with the in vivo findings, B7-H3 substantially augmented proinflammatory cytokine and chemokine production, upregulated NF-κB p65 and MAPK p38 phosphorylation, and enhanced the nuclear transactivation of NF-κB p65 at both TNF-α and IL-6 promoters in S. pneumoniae-stimulated primary murine microglia cells. These B7-H3-associated in vitro and in vivo effects appeared to be dependent on TLR2 signaling, as B7-H3 almost completely lost its amplifying actions in both TLR2-deficient microglial cells and TLR2-deficient mice. Furthermore, administration of the anti-B7-H3 mAb (MIH35) attenuated the inflammatory response and ameliorated blood-brain barrier disruption in S. pneumoniae-infected wild-type mice. Collectively, our results indicate that B7-H3 plays a contributory role in the development of S. pneumoniae infection-induced bacterial meningitis.