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

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $499,828

## Abstract

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 stud...

## Key facts

- **NIH application ID:** 10897154
- **Project number:** 5R01CA266099-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Dihua Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,828
- **Award type:** 5
- **Project period:** 2022-07-05 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897154

## Citation

> US National Institutes of Health, RePORTER application 10897154, Exploring the Function of MHC-II/Lag3 Axis in Brain Metastasis to Develop Novel Therapeutic Strategies (5R01CA266099-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10897154. Licensed CC0.

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