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Background Brain metastases is a fatal consequence of advanced breast cancer with a poor prognosis. Both tumor intrinsic molecular underpinning of the primary tumor and microenvironmental brain niche factors have been reported to allow invading cancer cells to colonize and outgrow into the brain. A systemic investigation of these tumor intrinsic and microenvironmental factors using same patient paired primary breast and brain metastatic tumor samples are warranted. Methods Nine pairs of primary breast and brain metastatic tumor samples were collected for RNA sequencing. Pairwise differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted. TCGA-BRCA (n=1222) dataset and a combined breast cancer cohort (n=2,765) were used for clinical and immune-infiltration correlation analysis. GSE12276 (n=204) dataset was used for brain-metastasis free survival correlation. Immunohistochemistry staining of HCMV was conducted on a total of 16 primary breast and brain metastatic tumor sections including 2 pairs. Two patient-derived xenograft (PDX) models were used for antiviral treatment and mechanism investigation. Results 371 up-regulated and 2,153 down-regulated genes in the 9 paired brain metastatic tumors vs. breast tumors (P< 0.05; log2 FC>1 or ←1) were identified from the RNAseq data. Reactome Human cytomegalovirus (HCMV) early and late events was the top enriched pathway for the 371 brain metastasis up-regulated genes, and Reactome IL4 and IL5 signaling was the top enriched pathway for the 2,153 primary breast tumor up-regulated genes. Among the 371 brain metastasis up-regulated genes, 287 genes are also up-regulated in primary breast cancer vs. normal breast in the TCGA 1222 cohort (P< 0.05). High expression of 23 out of the 287 genes are significantly associated with shorter distant metastasis-free survival (DMFS) in a combined breast cancer cohort of 2,765 patients (Logrank P< 0.05), and 19 of the 23 genes are associated with poor brain metastasis-free survival (BMFS) in the GEO dataset GSE12276 (n=204)(Logrank P< 0.05). We further identified that elevated expression of 12 out of the 19 genes are consistently associated with Th2 cell activation and NK cell deactivation in the TCGA 1222 cohort, for which the immunosuppressive Th2 cells are defined by secretion of IL4 and IL5 signature cytokines. Immunoreactive HCMV immediate early proteins indicating virus infection were examined in all the 16 patient tumor tissues, and strong positive signals were seen in both the paired breast tumor and brain metastatic specimens. Preventive treatment of anti-HCMV drug ganciclovir by suppressing viral DNA replication inhibited tumor colonization in the mouse brain in the two HCMV-positive PDX models. Conclusions Our systemic analysis of paired primary breast and brain metastatic tumor tissues identified a causal relationship between HCMV infection and reactivation, immunosuppressive Th2 cell activation and NK cell deactivation, and brain metastatic outgrowth. Since HCMV reactivation frequently induce encephalopathy during chemotherapy or radiation therapy, anti-HCMV agents may represent an effective strategy in preventing and controlling brain metastases. Citation Format: Xin Wang, Akshjot Puri, Amna Irfan, Kun Han, Wei Qian, Liliana Guzman, Roberto Rosato, Hong Zhao, Jenny Chang, Stephen Wong. Human Cytomegalovirus Reactivation in Immunosuppressive Th2 Tumor Microenvironment Facilitates Brain Metastatic Outgrowth [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD2-11. |
