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Targeting Nuclear LSD1 to Reprogram Cancer Cells and Reinvigorate Exhausted T Cells via a Novel LSD1-EOMES Switch
Wen Juan Tu1,2, Robert D McCuaig1,2, Abel H Y Tan2
1Gene Regulation and Translational Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Abstract:
Lysine specific demethylase 1 (LSD1) is a key epigenetic eraser enzyme implicated in cancer metastases and recurrence. Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) has been shown to be critical for the development of breast cancer stem cells. Here we show that circulating tumor cells isolated from immunotherapy-resistant metastatic melanoma patients express higher levels of nLSD1p compared to responders, which is associated with co-expression of stem-like, mesenchymal genes. Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552. We also demonstrate that nLSD1p is enriched in PD-1+CD8+ T cells from resistant melanoma patients and 4T1 immunotherapy-resistant mice. Targeting the LSD1p nuclear axis induces IFN-γ/TNF-α-expressing CD8+ T cell infiltration into the tumors of 4T1 immunotherapy-resistant mice, which is further augmented by combined immunotherapy. Underpinning these observations, nLSD1p is regulated by the key T cell exhaustion transcription factor EOMES in dysfunctional CD8+ T cells. EOMES co-exists with nLSD1p in PD-1+CD8+ T cells in resistant patients, and nLSD1p regulates EOMES nuclear dynamics via demethylation/acetylation switching of critical EOMES residues. Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.
Insights
Targeting nuclear LSD1 phosphorylated at serine 111 (nLSD1p) in cancer cells and T cells shows promise for overcoming immunotherapy resistance. This approach re-invigorates anti-tumor immunity and inhibits cancer stemness.
Area of Science:
- Epigenetics
- Cancer Biology
- Immunology
Background:
- Lysine specific demethylase 1 (LSD1) is an epigenetic enzyme involved in cancer progression.
- Nuclear LSD1 phosphorylated at serine 111 (nLSD1p) is crucial for breast cancer stem cell development.
- Immunotherapy resistance in metastatic cancers is a significant clinical challenge.
Purpose of the Study:
- To investigate the role of nLSD1p in immunotherapy-resistant melanoma.
- To evaluate the efficacy of targeting nLSD1p in preclinical models of cancer.
- To explore the interplay between nLSD1p, T cell exhaustion, and immunotherapy response.
Main Methods:
- Analysis of nLSD1p levels in circulating tumor cells and T cells from melanoma patients and mice.
- Inhibition of nLSD1p using selective inhibitors in cancer models.
- Assessment of gene expression, T cell infiltration, and cytokine production.
- Investigation of the regulatory relationship between nLSD1p and the transcription factor EOMES.
Main Results:
- Higher nLSD1p levels in circulating tumor cells from immunotherapy-resistant melanoma patients correlated with stem-like gene expression.
- Selective nLSD1 inhibitors effectively suppressed the stem-like mesenchymal signature.
- nLSD1p was enriched in PD-1+CD8+ T cells from resistant patients and mice.
- Targeting nLSD1p promoted CD8+ T cell infiltration and anti-tumor immunity, further enhanced by combination immunotherapy.
- nLSD1p regulates EOMES nuclear dynamics in dysfunctional CD8+ T cells, with reciprocal expression of EOMES post-translational modifications observed in resistant vs. responder patients.
Conclusions:
- nLSD1p is a critical mediator of immunotherapy resistance in metastatic melanoma.
- Targeting the nLSD1p axis offers a dual therapeutic strategy for inhibiting cancer stemness and reinvigorating anti-tumor immunity.
- This approach holds potential for overcoming resistance to current immunotherapies.
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