Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells

Wang et al., 2024, Cancer Cell 42, 1–16

In the new era of cancer treatment, immunotherapy has become a revolutionary therapeutic approach. Particularly, immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 antibodies have significantly improved the survival rates of patients with various types of cancer.

Immune checkpoint inhibitors enhance the body’s immune response to cancer cells by blocking inhibitory signals on T-cells. Although these therapies have shown remarkable efficacy in certain patients, understanding of their cellular and molecular mechanisms remains limited. Notably, the combination of anti-PD-1 and anti-CTLA-4 therapies has shown better efficacy in metastatic melanoma than monotherapy, but the mechanisms behind it are not well understood.

Recently, a study published in the journal Cancer Cell has provided new insights into how the combination of these two antibodies can activate CD8+ T-cell clonal responses.

The paper, titled “Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells” was published on September 9, 2024, in Cancer Cell by Kevin Wang and colleagues. The study primarily investigated the efficacy of the combination therapy with anti-PD-1 and anti-CTLA-4 antibodies in melanoma patients, especially how it affects the clonal response of CD8+ T cells.

The research team conducted longitudinal blood sample analysis on 36 patients with stage IV melanoma who received anti-PD-1, anti-CTLA-4, or combination therapy. They employed single-cell RNA sequencing and T-cell receptor (TCR) sequencing technologies and developed an algorithm named Cyclone to track clonal dynamics over time.

The study found that new T-cell populations were generated in patients with each administration of combination therapy. The research team referred to this phenomenon as “clonal response waves,” meaning that the treatment not only relies on existing T-cells but also continuously mobilizes new immune cells to join the fight. These response waves peaked at 3, 6, and 9 weeks after treatment, indicating different patterns of immune activation at various time points. Notably, anti-CTLA-4 therapy significantly promoted the expansion and proliferation of progenitor-exhausted CD8+ T cells (TEX), which synergized with anti-PD-1 therapy to reactivate TEX in combination therapy. The researchers also found that anti-CTLA-4 therapy could induce the production of potent TEX, which may be related to the expression of CTLA-4 on TEX.

These findings not only reveal how combination immunotherapy activates specific T-cell clones but also point out the key role of anti-CTLA-4 therapy in promoting the expansion of TEX. This is significant for understanding the efficacy of combination therapy and optimizing future treatment strategies. Additionally, by analyzing clonal trajectories, researchers were able to distinguish different dimensions of immune responses, which is important for understanding the dynamic changes in treatment and optimizing treatment plans.

This study provides an in-depth understanding of how combination immunotherapy affects CD8+ T-cell clonal responses and offers valuable information for future cancer immunotherapy strategies. Nevertheless, the study’s small sample size and lack of direct correlation with clinical outcomes indicate the need for further research to validate these findings and explore how to translate this knowledge into more effective treatment strategies.

In the sample preparation phase of the study, cells were stained with 60 or 101 Total-Seq-C antibodies at room temperature for 30 minutes, followed by washing with the Curiox Laminar Wash™ HT1000 system. Laminar wash technology has unparalleled advantages for washing cells stained with Total-Seq-C antibodies, with a gentle and efficient washing process that can effectively reduce cell damage, keeping cells more active, while effectively removing unbound antibodies, greatly enhancing the accuracy of detection.

Laminar Wash™ Technology
Curiox Laminar Wash™ Technology
Subscribe to our newsletter

Get updates about upcoming webinar technical application information and product announcements when you subscribe to the Curiox newsletter.