What Is The Role of CD38 in Restoring T Cell Function?

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What Is The Role of CD38 in Restoring T Cell Function?

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What Is The Role of CD38 in Restoring T Cell Function?

New Discovery at Massachusetts General Hospital! Unlocking the Mystery of Drug Resistance by CD38!

Introduction

A recent publication from the Cancer Center at Massachusetts General Hospital in the United States on February 14, 2024, reveals the key factors in the development of resistance to immune checkpoint therapy.

The study suggests that the core issue leading to resistance in immune checkpoint blockade (ICB) cancer immunotherapy is T-cell exhaustion caused by chronic antigen exposure in the tumor microenvironment. CD38, as an extracellular enzyme related to NAD+ metabolism, is associated with ICB resistance in melanoma and plays a crucial role in regulating CD8+ T cell function. Targeting CD38 can restore cell function, enhance immunity, overcome ICB resistance, and bring new strategies for treatment.

Although immune checkpoint blockade (ICB) cancer immunotherapy has provided durable responses and cures for some patients with late-stage metastatic diseases, resistance to ICB remains a significant challenge. Currently, there are no approved treatments, so new therapeutic strategies are needed to overcome this challenge.

The heterogeneity of CD8+ T cells within tumors is critical for the efficacy of ICB, and single-cell sequencing has revealed the characteristics of enriched CD8+ T cells and exhausted CD8+ T cells in different types of patients. Exhausted T cells may result from chronic antigen stimulation, and treatment strategies should focus on promoting the expansion of stem cell-like T cells, enhancing effector function, and preventing or reversing T cell exhaustion to address ICB resistance. Studies indicate that the regulation of CD38 is closely related to tumor infiltration, T cell homeostasis, and ICB resistance. Targeting CD38 may help overcome these issues, restore T cell function, and enhance ICB sensitivity.

CD38 + CD8 + TILs Predict ICB Resistance

The study analyzed the expression of CD38 in tumor-infiltrating CD8+ T cells using single-cell RNA sequencing data and found that CD38 expression is associated with T cell exhaustion, closely related to PD-1 expression, and associated with ICB resistance, as well as related to the TCF7 transcription factor, showing a high predictive ability for ICB resistance, associated with resistance to PD-1 inhibition and PD-1/CTLA-4 dual blockade.

Data related to CD8 + T cells and ICB resistance.

In melanoma, tumor-infiltrating CD8+ T cell cluster 6 has the highest predictive ability for ICB treatment resistance, while the expression of CD38 in CD8+ T cells in different cancer types is associated with the lack of benefit from ICB therapy.

Particularly, enrichment of CD38 expression is observed in exhausted T cell clusters, suggesting a possible association with the effectiveness of ICB therapy.

ICB Treatment Increases CD38 T Cells

ICB therapy affects Cd38 expression in CD8+ T cells, and studies show that anti-PD-1 therapy can lead to early effector CD8+ T cell expansion and a significant increase in Cd38 expression in terminal exhausted/effector CD8+ T cells.

CD38 Blockade Overcomes ICB Resistance

Research indicates that upregulation of CD38 in CD8+ T cells is associated with T cell dysfunction and ICB resistance, while CD38 deficiency can promote the restoration of T cell effector function.

Therefore, researchers are considering CD38 blockade as a strategy to overcome ICB resistance and have conducted ex vivo analyses of patient-derived organotypic tumor spheroids (PDOTS).

The results show that dual PD-1/CD38 blockade significantly reduces the activity of PDOTS, with better efficacy in patients with ICB resistance than single-agent PD-1 blockade.

Restoring NAD+ to Overcome ICB Resistance

The response rate to PD-1/CD38 dual blockade is higher, while the response rate to single-agent PD-1 blockade is lower, especially in patients with ICB-resistant tumors observed to have a specific ex vivo response to dual blockade.

The study found that upregulation of CD38 in CD8+ T cells is associated with T cell dysfunction and ICB resistance, and CD38 deficiency can promote the restoration of T cell effector function.

Therefore, researchers are considering CD38 blockade as a strategy to overcome ICB resistance and have conducted ex vivo analyses of patient-derived organotypic tumor spheroids (PDOTS). Treatment with anti-PD-1 pembrolizumab +/- anti-CD38 daratumumab significantly reduced the activity of PDOTS, with better efficacy in patients with ICB resistance than single-agent PD-1 therapy.

Discussion and Conclusion

CD38 + CD8 + T cells play a crucial role in ICB resistance, and the genetic loss or inhibition of CD38 can restore T cell function by affecting multiple cellular processes, including mitochondrial function and gene transcription, thereby improving T cell effector function. In addition, the metabolism regulation of NAD+ also affects the expression of TCF7 in tumor-infiltrating CD8+ T cells, although its impact on the memory status of these cells is not yet clear.

CD38 is an important factor in the process of T cell exhaustion under conditions such as cancer and chronic viral infections, and its expression is influenced by transcriptional regulation. The study found that CD38 is highly expressed in exhausted T cells, particularly in patients with hepatitis C. Although CD38 is co-expressed with other exhaustion markers, its regulatory mechanisms and reversibility require further investigation, particularly regarding its expression after treatment.

Melanoma and other cancers face challenges of resistance when using ICB cancer immunotherapy, although some patients can benefit from existing second-line combination therapies. Studies suggest that PD-1/CD38 dual blockade is effective in ex vivo tumor models derived from patients with clinical ICB resistance, supporting further development of therapeutic strategies targeting CD38 to address resistance. Furthermore, CD38 monoclonal antibodies have been approved by the FDA for other indications, providing a clear pathway to rapidly translate these findings into clinical trials.

What Is The Role of CD38 in Restoring T Cell Function?

(source:internet, reference only)

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