Abstract B20: Peritumoral CD3+ lymphocyte infiltration at the brain-brain metastasis interface is detectable by diffusion MRI and independently associated with prolonged survival
Authors: Zakaria Rasheed , Jenkinson Michael D. , Rudland Philip S. 
Published: March 2017

Abstract
Brain metastases are an increasing clinical problem, causing significant morbidity and mortality in patients with solid organ cancer. Diffusion along white matter tracts can be assessed by diffusion tensor MRI (DTI) and disruption of white matter tract integrity generally indicates tumor invasion and inflammation in the brain. Matched preoperative DTI and image-guided neurosurgical sampling of the brain-brain metastasis interface was performed in 26 adult patients undergoing resection of a brain metastasis, uniquely yielding paired MRI and biological data from the same regions. Patients were followed prospectively from imaging diagnosis until death. In this surgical series patients were mostly of excellent performance status with no or stable primary disease. We consistently observed dense, activated macrophage infiltration at the brain-brain metastasis interface across tumors from different primaries. CD20-positive, B cell infiltration was sparse (with no significant difference from control white matter). CD3-positive lymphocytes were seen in the peritumoral region in all except 1 case (median 16 cells per high power field (HPF), significantly greater than control white matter, p&lt;0.001). Peritumoral density of these cells, but not edge or core density and not peritumoral macrophage or B-cell infiltration, was associated with prolonged survival, even when controlling for confounders such as adjuvant whole brain radiotherapy (Cox proportional hazards analysis, HR = 0.96, 95% CI 0.93-0.99, p=0.021). When this CD3-positive lymphocyte response was further categorized into three groups (&lt;5, 5-25 and &gt;25 immunoreactive cells/HPF), those with moderate peritumoral infiltration were at no survival advantage compared to those with low infiltration, whereas those with the highest infiltrates lived over twice as long (median 11.7 months, vs. 5.1 and 5.2 months for moderate and low groups respectively, log rank test=10.06, p=0.007). Using image analysis of the paired MRI data, average fractional anisotropy (FA) readings in the peritumoral region were significantly lower than the unaffected, contralateral hemisphere indicating white matter disruption (related samples Wilcoxon-signed rank test, p&lt;0.001). Those patients with a lower peritumoral FA (below median), indicating more white matter tract disruption, showed longer survival (median 9.9 months, 95% CI: 7.4-12.4 versus 5.3 months, 95% CI: 3.4-7.1) even if confounding variables were accounted for (HR = 0.21, 95% CI 0.06-0.96, p=0.044). The peritumoral density of CD3-positive lymphocytes was the only significant biological difference observed between the cases with high and low peritumoral FA i.e. metastases with less or more white matter tract disruption around them (Mann Whitney U, p=0.037). There were no differences in the presence of other immunoreactive cells, primary cancer type, growth pattern (invasive or pseudo-encapsulated), expression of matrix-metallo-proteinases, cellularity, Ki67 proliferative index, vascularity, necrosis or connective tissue density at the leading edge of the tumor or adjacent peritumoral region in those metastases with lower as opposed to higher peritumoral FA readings. Overall this unique data suggests that the cellular immune response to brain metastases is robust, may be a marker of subsequent overall survival and can be assayed non-invasively by measuring white matter tract disruption at DTI.
Citation Format: Rasheed Zakaria, Michael D. Jenkinson, Philip S. Rudland. Peritumoral CD3+ lymphocyte infiltration at the brain-brain metastasis interface is detectable by diffusion MRI and independently associated with prolonged survival. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B20.