Tmem33 mediates cell-intrinsic immunosuppression of CD8+ T cells

Thesis

The Transmembrane Protein 33 (TMEM33), an endoplasmic reticulum (ER)-resident protein, regulates calcium homeostasis, misfolded protein degradation, and innate immune signalling. In cancer, high tumour cell TMEM33 expression has been linked to adverse prognoses, accelerated tumour progression, and impaired immune infiltration. However, the underlying mechanisms and the role of TMEM33 in immune cells remain largely unclear. Our lab’s previous work established that genetic deletion of Tmem33 (Tmem33⁻^/⁻) in mice led to delayed tumour growth and enhanced CD8⁺ T cell infiltration and fitness within the tumour microenvironment (TME) in a melanoma model. This study aims to address the gap in understanding how Tmem33 impacts CD8⁺ T cells and the molecular mechanisms involved. Bulk RNA sequencing of tumour-infiltrating CD8⁺ T cells from Tmem33⁻^/⁻ mice revealed a marked upregulation of terms associated with T cell receptor (TCR) signalling pathways, suggesting augmented T cell activation. Ex vivo experiments demonstrated that Tmem33 deficiency had limited impact on antigen presentation by bone marrow-derived dendritic cells (BMDCs) or the activation profiles of CD4⁺ T cells. In contrast, loss of Tmem33 enhanced the functional characteristics and proliferative capacity of splenic CD8⁺ T cells and isolated naïve CD8⁺ T cells. This was evidenced by increased expression of both surface activation markers (CD25, CD44, CD137) and effector molecules (GZMB, IFN-γ, TNF-α). Mechanistically, upon stimulation, Tmem33 deficiency in naïve CD8⁺ T cells lead to stronger calcium signalling. Collectively, these data establish Tmem33 as a novel cell-intrinsic immunoregulatory molecule within CD8⁺ T cells. Future work will further investigate the specific molecular targets impacted and validate Tmem33’s immunoregulatory role using a broader range of preclinical models.

Authors: Zhao, T

• DOI: 10.5287/ora-nz0wrxeav
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: TMEM33; TME; tumour; T cell; melanoma
• Subjects: Immunology; Oncology