Abstract 6620: Identification of crosstalk signaling between brain-tumor niche and reactive human cytomegalovirus in brain metastases
Authors: Wang Xin , Akshjot Puri , Han Kun , Irfan Amna , Guzman Liliana , Qian Wei , Rosato Roberto , Zhao Hong , Chang Jenny , Wong Stephen 
Published: June 2023

Purpose: Human cytomegalovirus (HCMV) is a common neurotropic herpes virus although its DNA was confirmed highly prevalent in various peripheral cancers. HCMV is also a major cause of neuropathology in immune-compromised patients. Since HCMV reactivation frequently causes encephalopathy during chemotherapy or radiation therapy in brain tumor patients, understanding the brain niche-HCMV crosstalk signaling may pinpoint effective strategies in managing brain metastases.

Methods: We collected nine pairs of primary breast and brain metastatic tumor samples from our institution and analyzed their RNA-Seq data. Pairwise differential gene expression analysis and gene set enrichment analysis (GSEA) were conducted. TCGA-BRCA (n=1,222) dataset was 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 sixteen primary breast and brain metastatic tumor sections and an 86-core tissue microarray (TMA) of human brain metastasis tissue. CCCExplorer software was used to explore molecular crosstalk signaling between the secretome proteins from HCMV-infected cells and brain metastatic niche cells.

Results: Reactome Human cytomegalovirus (HCMV) early and late events was the top enriched pathway for the 371 brain metastasis up-regulated genes while 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&lt;0.05). High expression of 19 out of the 287 genes are significantly associated with poor brain metastasis-free survival in the GSE12276 cohort (Logrank P&lt;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 1,222 cohort, for which immunosuppressive Th2 cells are defined by secretion of IL4 and IL5 signature cytokines. Immunoreactive HCMV reactivation proteins were examined in the paired breast tumor and brain metastatic specimens, and most of the TMA tumors. Preventive treatment of an anti-HCMV drug, ganciclovir, by suppressing viral DNA replication inhibited tumor colonization in the mouse brains of the two HCMV-positive PDX models. Several HCMV cell-entry co-receptors are highly expressed in brain metastatic niche. Furthermore, from the secretome of HCMV-infected cells, we identified 89 paired receptors that potentially regulate niche cell behaviors.

Conclusions: Our systemic analysis revealed a causal relationship between HCMV reactivation and brain metastatic outgrowth. Targeting the key brain-tumor niche-HCMV crosstalk signaling may benefit the management of brain metastases.

Citation Format: Xin Wang, Puri Akshjot, Kun Han, Amna Irfan, Liliana Guzman, Wei Qian, Roberto Rosato, Hong Zhao, Jenny Chang, Stephen Wong. Identification of crosstalk signaling between brain-tumor niche and reactive human cytomegalovirus in brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6620.