CD5 Expression Dynamically Changes During the Differentiation of Human CD8⁺ T Cells Predicting Clinical Response to Immunotherapy

Abstract

Defining the molecular dynamics associated with T cell differentiation enhances our understanding of T cell biology and opens up new possibilities for clinical implications. In this study, we investigated the dynamics of CD5 expression in CD8 + T cell differentiation and explored its potential clinical uses. Using PBMCs from 29 healthy donors, we observed a stepwise decrease in CD5 expression as CD8 + T cells progressed through the differentiation stages. Interestingly, we found that CD5 expression was initially upregulated in response to T cell receptor stimulation, but diminished as the cells underwent proliferation, potentially explaining the differentiation-associated CD5 downregulation. Based on the proliferation-dependent downregulation of CD5, we hypothesized that relative CD5 expression could serve as a marker to distinguish the heterogeneous CD8 + T cell population based on their proliferation history. In support of this, we demonstrated that effector memory CD8 + T cells with higher CD5 expression exhibited phenotypic and functional characteristics resembling less differentiated cells compared to those with lower CD5 expression. Furthermore, in the retrospective analysis of PBMCs from 30 non-small cell lung cancer patients, we found that patients with higher CD5 expression in effector memory T cells displayed CD8 + T cells with a phenotype closer to the less differentiated cells, leading to favorable clinical outcomes in response to immune checkpoint inhibitor (ICI) therapy. These findings highlight the dynamics of CD5 expression as an indicator of CD8 + T cell differentiation status, and have implications for the development of predictive biomarker for ICI therapy.

Exploring GZMK as a Prognostic Marker and Predictor of Immunotherapy Response in Breast Cancer: Unveiling Novel Insights into Treatment Outcomes

“…Understanding the molecular dynamics of T cell differentiation contributes to advancing our knowledge of T cell biology and opens up new possibilities for clinical applications. In a retrospective analysis of non-small cell lung cancer (NSCLC) patients receiving anti-PD-1/PD-L1 therapy, patients with higher expression of CD5 on their effector memory T cells (Tem) showed improvement in response to anti-PD-1/PD-L1 therapy compared to those with lower CD5 expression [33] . Similarly, studies have demonstrated that Treg cells inhibit the activity of NK and CD8 + T cells through the GZMB-perforin pathway, and GZMB-deficient mice are more effective than wild-type (WT) mice in clearing both allogeneic and syngeneic tumor cell lines [34] .…”

Exploring GZMK as a prognostic marker and predictor of immunotherapy response in breast cancer: unveiling novel insights into treatment outcomes

“…Understanding the molecular dynamics of T cell differentiation advances our knowledge of T cell biology and opens new possibilities for clinical applications. In a retrospective analysis of non-small cell lung cancer (NSCLC) patients undergoing anti-PD-1/PD-L1 therapy, those with higher CD5 expression on their effector memory T cells (Tem) showed improved responses compared to those with lower expression (Kim et al 2023 ). Studies also show that Treg cells inhibit the activity of NK and CD8 + T cells through the GZMB-perforin pathway, and GZMB-deficient mice are more effective in clearing both allogeneic and syngeneic tumor cell lines (Cao et al 2007 ).…”

IL-15 in T-Cell Responses and Immunopathogenesis

“…Recently, CD5 was shown to function as a negative regulator of the IL-15 response in memory CD8 + T cells ( 66 ). The expression of CD5 on human CD8 + T cells progressively decreases during cellular differentiation and senescence ( 68 69 ). Consequently, highly differentiated and senescent memory CD8 + T cells with low expression of CD5 exhibit a heightened responsiveness to IL-15, revealing an inverse correlation between the level of CD5 expression and IL-15 responsiveness.…”