Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis.

Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs' contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-κB and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.

Digital health technology utilization is associated with enhanced patient perspectives of care.

BACKGROUND: Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores measure patient experience and perspectives on care. Novel health information technologies facilitate communication between patients and healthcare teams. Playback Health is a health information technology that incorporates multimedia for providers to communicate health information to patients, their support network, and their healthcare teams. We hypothesized implementing Playback Health may enhance patient perspectives on care. METHODS: HCAHPS scores were obtained retrospectively from a neurosurgical practice located in a metropolitan area between 2020 and 2022 for seven providers. Of these, four providers utilized Playback Health, and three did not. Individual providers' scores were compared between domains using two tailed t-tests at a significance level of p < 0.05. RESULTS: Playback Health use was associated with higher HCAHPS scores across varying domains from 2020 through 2022 as well as overall scores. In 2020, the mean overall score of HCAHPS users was higher than non-users (89.65 vs. 87.28, p = 0.0095). In 2021, again higher mean overall scores were observed in users as compared to non-users (89.11 vs. 87.79, p 0.0266). In 2022, Playback Health users maintained higher scores across communication domains and overall scores (p < 0.00001). Comparisons within domains between Playback Health users and non-users revealed no domains in which non-users had a significantly higher score than users. CONCLUSION: The addition of Playback Health multimedia health information technology was associated with improved patient satisfaction scores. When used as an adjunct to existing patient care, multimedia health information technologies may improve patient perceived care.

SRRM4-mediated REST to REST4 dysregulation promotes tumor growth and neural adaptation in breast cancer leading to brain metastasis.

BACKGROUND: Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases (BBMs) has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Serine/Arginine Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells. METHODS: Utilizing pure neuronal cultures and brain-naive and patient-derived BM tumor cells, along with in vivo tumor modeling, we surveyed the early induction of mediators of neural acclimation in tumor cells. RESULTS: When SRRM4 is overexpressed in systemic breast cancer cells, there is enhanced BBM leading to poorer overall survival in vivo. Concomitantly, SRRM4 knockdown expression does not provide any advantage in central nervous system metastasis. In addition, reducing SRRM4 expression in breast cancer cells slows down proliferation and increases resistance to chemotherapy. Conversely, when SRRM4/REST4 levels are elevated, tumor cell growth is maintained even in nutrient-deprived conditions. In neuronal coculture, decreasing SRRM4 expression in breast cancer cells impairs their ability to adapt to the brain microenvironment, while increasing SRRM4/RE-1 Silencing Transcription Factor (REST4) levels leads to greater expression of neurotransmitter and synaptic signaling mediators and a significant colonization advantage. CONCLUSIONS: Collectively, our findings identify SRRM4 as a regulator of brain metastasis colonization, and a potential therapeutic target in breast cancer.