Exploring the Function of MHC-II/Lag3 Axis in Brain Metastasis to Develop Novel Therapeutic Strategies

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Summary Brain metastasis (BM) affects millions of cancer patients and represents an unmet clinical challenge. Advances in targeted- and immuno-therapies have prolonged cancer patients’ survival via better control of primary cancers and extracranial metastases, but the incidence of BM is increasing steadily upon disease recurrence. Sadly, patients having symptomatic BMs do not respond well to current treatments and have extremely poor survivals. The brain has unique structural and biological features, thus the interaction of BM tumor cells with the brain physical environment are distinctive and underexplored. Deeper understanding of these unique interactions is critical for developing better therapeutics for BM. Recently, we found that microglia, which are myeloid-derived innate immune cells in the brain, were activated upon BM cell extravasation into the brain parenchyma. Further, Lag3 on microglia binds to the major histocompatibility complex (MHC)-II on BM cancer cells, and this interaction inhibits early-stage BM outgrowth. Interestingly, MHC-II is severely downregulated in human and mice BMs compared to their primary tumors. MHC-II genes are known to be silenced by epigenetic modifications in cancer cells, e.g., EZH2-induced 3meK27H3, or increased histone deacetylase (HDAC) function. Indeed, knockout EZH2 in cancer cells increased BM cell surface MHC-II molecules and decreased BM growth in mice; and treating cancer cells with clinically-applicable EZH2- and/or HDAC-inhibitors increased MHC-II expression. These findings led us to hypothesize that MHC-II on BM cells and Lag3 on microglia dynamically interact to control early-stage BM outgrowth, and restoring MHC-II expression in BM using epigenetic drugs may boost brain innate immune responses and provide novel strategies to treat BM. We will test our hypothesis by interrogating how microglia, a unique innate immune component in the brain, interact with BM tumor cells along the temporo-spatial progression of BM. Also, early-stage BM biology is severely understudied, since most surgically resected patients’ BMs are late-stage lesions. We will explore the interaction between BM and the unique brain environment during BM development and discover novel biological determinants that are critical for early-stage BM using enhanced MRI imaging to precisely locate early stage BM lesions, and by spatial gene expression profiling (Aim 1). To uncover mechanisms that boost the innate immune response in early stage BM, we will assess how the tumoral MHC-II/microglial Lag3 interaction functionally controls BM outgrowth and we will elucidate the epigenetic regulation of MHC-II expression in BM cells (Aim 2). Lastly, we will test whether therapeutically increasing MHC-II with clinically-applicable epigenetic drugs boosts immunity and inhibits BM in preclinical models and test the potential synergy of combining epigenetic modulators with existing immune checkpoint therapies (Aim 3). In summary, our proposed studies focus on revealing the dynamic interactions and crosstalk of BM cells with the innate immune compartment within the brain and developing novel early intervention and therapeutic strategies using epigenetic drugs to enhance the immune response and treat BMs.