Biology subjects

Phyu, S. M.

Publications and source records attributed to Phyu, S. M..

3 recordsLinked to original sources

bioRxiv2026

TMEM33 deletion potentiates anti-tumor CD8+ T cell immunity

Improving responses to cancer immunotherapies requires deeper insight into the cellular mechanisms governing T cell-mediated anti-tumor immunity. TMEM33 is an endoplasmic reticulum-resident transmembrane protein enriched across multiple tumor types, with reported functions in anti-viral immunity as well as calcium and lipid homeostasis, yet its role in tumor immunosurveillance remains unknown. Using murine genetic models, we demonstrate that host TMEM33 constrains anti-tumor CD8+ T cell responses. Constitutive Tmem33-/- mice exhibited delayed melanoma tumor growth and increased CD8+ T cell infiltration. Antigen-specific CD8+ compartments in tumors of Tmem33-/- mice showed TCF-1+PD-1+ progenitor-exhausted cell (Tpex) enrichment, elevated effector function and reduced exhaustion, alongside improved effector memory expansion and T-bet expression in draining lymph nodes. We highlight that TMEM33 functions intrinsically within the T cell compartment, as TMEM33 deletion (1) enhanced polyclonal activation of naive CD8+ T cells ex vivo, (2) promoted preferential Tpex accumulation among adoptively transferred naive OT-I cells in B16F10-OVA tumors and draining lymph nodes, and (3) improved the potency of ex vivo-expanded OT-I cells in controlling tumor growth during adoptive cell therapy. Finally, in a large, prospectively recruited metastatic melanoma cohort, lower TMEM33 expression in patient CD8+ T cells significantly correlated with improved survival and elevated TCF-7 (encoding TCF-1). Collectively, our findings define TMEM33 as a formerly unrecognized intrinsic determinant of tumor-directed CD8+ T cell fate that limits Tpex maintenance, and restrains cell therapy responses, suggesting that its modulation may strengthen immunotherapeutic efficacy. One sentence summaryTMEM33 intrinsically limits progenitor exhausted CD8+ T cells, scales anti-tumor responses and predicts melanoma patient survival.

immunology↗

bioRxiv2024

IGFs regulate cancer cell immune evasion in prostate cancer

Insulin-like growth factor-1 (IGF-1) promotes prostate cancer (PCa) development and lethality, with immunosuppressive properties in other disease models. These studies investigated the tumor-intrinsic immune effects of IGF-1 in PCa to understand mechanisms underlying its poor immunotherapy response. Transcriptional profiling of human (DU145, 22Rv1) and murine (Myc-CaP) PCa cells revealed, through pathway enrichment, that cytokine signalling, antigen processing and presentation, and other immune regulatory pathways, were most suppressed by IGF-1. We went on to investigate changes in the expression of components of two key pathways responsible for cancer cell recognition by immune cells and immune evasion: antigen processing and presentation, and PD-L1 checkpoint expression. These pathways are crucial for determining immunotherapy response. IGF-1 downregulated transporters associated with antigen processing (TAPs), endoplasmic reticulum aminopeptidase-1 (ERAP-1), and Class I component {beta}2-microglobulin, without major changes in Class I allele expression. These effects were associated with reduced presentation of Class I complexes on the Myc-CaP cell surface suggesting altered peptide transport, processing, and/or presentation. In contrast, IGF-1 upregulated immune checkpoint CD274 (PD-L1) via IGF receptor/AKT/ERK-dependent signaling. Analysis of public data (TCGA Firehose Legacy PCa) revealed increased CD274 expression in PCa with high endogenous IGF1 and IGFBP5, markers of high IGF axis activity. Additionally, in primary PCa (n=32), multiplex immunofluorescence revealed higher PD-L1 expression in the central tumor of men with high serum IGF-1 promoting cancer cell immune evasion in PCa. These findings indicate a novel mechanism by which IGF-1 mediates immunosuppressive effects in malignant prostate epithelium, potentially explaining the poor responsiveness of PCa to immunotherapy and highlighting the complex interplay between IGF signaling and immune evasion.

cancer biology↗

bioRxiv2020

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

cancer biology↗