Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

A better understanding of immune response in breast cancer brain metastases (BCBM) may prompt new preventive and therapeutic strategies. Immunohistochemical expression of stromal tumor-infiltrating lymphocytes (TILs: CD4, CD8, CTLA4), macrophage/microglial cells (CD68), programmed cell death protein 1 receptor (PD-1), programmed cell death protein 1 receptor ligand (PD-L)1, PD-L2 and glial fibrillary acid protein was assessed in 84 BCBM and their microenvironment. Median survival after BCBM excision was 18.3 months (range 0–99). Median number of CD4+, CD8+ TILs and CD68+ was 49, 69 and 76 per 1 mm2, respectively. PD-L1 and PD-L2 expression in BCBM was present in 53 % and 36 % of cases, and was not related to BCBM phenotype. PD-1 expression on TILs correlated positively with CD4+ and CD8+ TILs (r = 0.26 and 0.33), and so did CD68+ (r = 0.23 and 0.27, respectively). In the multivariate analysis, survival after BCBM excision positively correlated with PD-1 expression on TILs (hazard ratio (HR) = 0.3, P = 0.003), CD68+ infiltration (HR = 0.2, P < 0.001), brain radiotherapy (HR = 0.1, P < 0.001), endocrine therapy (HR = 0.1, P < 0.001), and negatively with hormone-receptor-negative/human epidermal growth factor receptor 2 (HER2)-positive phenotype of primary tumor (HR = 2.6, P = 0.01), HER2 expression in BCBM (HR = 4.9, P = 0.01). PD-L1 and PD-L2 expression is a common occurrence in BCBM, irrespective of primary tumor and BCBM phenotype. Favorable prognostic impact of PD-1 expression on TILs suggests a beneficial effect of preexisting immunity and implies a potential therapeutic role of immune checkpoint inhibitors in BCBM.

Tumor-infiltrating lymphocytes (TILs) are pivotal in the immune response against breast cancer (BC), with their prognostic and predictive significance varying across BC subtypes. In triple-negative BC (TNBC), higher TIL levels correlate with improved prognosis and treatment response, guiding therapeutic strategies and potentially offering avenues for treatment de-escalation. In metastatic TNBC, TILs identify patients with enhanced immunotherapy response. HER2+ BC, similar to TNBC, exhibits positive correlations between TILs and treatment response, especially in neoadjuvant settings. Luminal BC generally has low TILs, with limited prognostic impact. Single hormone receptor-positive BCs show distinct TIL associations, emphasizing subtype-specific considerations. TILs in ductal carcinoma in situ (DCIS) display ambiguous prognostic significance, necessitating further investigation. Standardizing TIL assessment methods is crucial for unlocking their full potential as biomarkers, guiding treatment decisions, and enhancing patient care in BC.

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

Introduction: Granulomatosis with polyangiitis (GPA) is a rare, ANCA-associated, systemic disease characterized by necrotizing small and medium vessel vasculitis of unknown etiology associated with granulomatous inflammation affecting the renal, pulmonary, upper airways, ocular systems and other tissues. Histological proof of the granulomatosis with polyangiitis (GPA) can be obtained by biopsy of clinically involved sites. The main purpose of this study was to examine histopathological changes in non-renal biopsies from patients with established diagnosis of GPA and evaluated the histological confirmation at diagnosis of this disease. Material and methods: A retrospective analysis was performed in patients with GPA diagnosed and treated in clinics of the University Clinical Center (UCK) in Gdansk in 1988–2009. Results: In the analyzed group of GPA patients the histopathological examination of biopsies taken from involved tissues (except kidney) was performed in 60% of patients. Thirty-six out of 93 biopsies (39%) were diagnosed as typical of GPA, 10 (10.7%) were suggestive and 51 (54.8%) were non-specific. Considering all biopsies, the diagnosis was confirmed in 24 patients (57% of patients in whom biopsies were taken). Epitheloid cell granulomas were present in 33 biopsies (43%), characteristic necrosis in 27 biopsies (35%), small vessel vasculitis in 18 biopsies (23%), while multinucleated giant cells were identified only in 9 biopsies (12%). Conclusions: Histopathological examination of the affected tissues remains the gold standard of the diagnosis of GPA. Its usefulness increases, particularly in ANCA-negative patients, in the initial phase of the disease, or in patients with atypical clinical presentation. In many cases, it is necessary to repeat biopsy to establish the diagnosis. The role of the histopathological examination seems to be particularly important when ANCA is negative or clinical symptoms are atypical of GPA.