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UK Researchers Show Cytotoxic T-Cell Level Predicts Melanoma Immunotherapy Response

NEW YORK – Melanoma patients harboring higher numbers of a specific type of CD8-positive T cells may be more likely to respond to immune checkpoint inhibitors, according to research published Friday in Science Immunology.

The study, conducted by a group of researchers from the University of Oxford and the University of Cambridge, could represent an important step toward understanding why certain patients respond well to immune checkpoint inhibitors, such as Merck's anti-PD-1 agent pembrolizumab (Keytruda) and Bristol Myers Squibb's anti-PD-1-CTLA4 combination, nivolumab (Opdivo) plus ipilimumab (Yervoy), while others do not.

Specifically, the Science Immunology paper's lead author Robert Watson and colleagues found that metastatic melanoma patients with larger numbers of cytotoxic T-cell clones at baseline experienced improved progression-free survival when treated with immune checkpoint inhibitors, whereas patients whose T cells had a lower cytotoxic profile before treatment were less likely to derive this increased benefit.

To conduct their study, researchers first analyzed peripheral blood samples from eight metastatic melanoma patients: four undergoing treatment with pembrolizumab and four receiving the nivolumab-ipilimumab combination. Using single-cell RNA sequencing, Watson and colleagues analyzed patients' samples collected before treatment and 21 days after starting treatment, and identified seven distinct groups of CD8-positive T cells.

These included naïve, central memory T cells, effector memory T cells, effector cells, mitotic cells, γδ T cells, and KLRB1-expressing mucosal-associated invariant T cells, which formed a separate cluster from the rest of the cells. Among these groups, the effector memory T cells and the effector cells were found to have a greater degree of cytotoxic signaling, and were more likely to persist following immunotherapy treatment.

The researchers homed in on differentially expressed genes to determine the relationship between the clonal size of patients' T cells and their outcomes on checkpoint inhibitors. Here, they found that large clones were correlated with a greater magnitude of benefit with the therapy. They reported that both the clone size and the cytotoxic profile of the patients' immune cells at baseline could impact immunotherapy response.

To validate their findings, the researchers analyzed an external dataset with paired RNA sequencing and T-cell receptor (TCR)-beta chain sequencing data. Measuring the expression of a set of genes with the most significant correlations with cytotoxicity — including CD3D, CD3E, CD8A, CD8B, IFNG, and PRF1 — they found that patients with below-median large clone counts and cytotoxicity at baseline had significantly lower overall survival when treated with checkpoint inhibitors. The researchers further confirmed these findings in a larger cohort of nearly 200 samples.

Ultimately, Watson and colleagues concluded that the effector memory T-cell subset expands both in peripheral blood and in the tumor when patients are treated with checkpoint inhibitors, and is most likely to persist following treatment. Accordingly, the authors wrote, the effector T-cell compartment seems to be most sensitive to immune checkpoint inhibition, and the large effector cell clones were "likely reflective of successful [T-cell receptor] ligation and subsequent expansion … [suggesting] that the increased sensitivity to [these drugs] reflects intrinsic activity of these clones."

The authors further said their analysis may point to strategies for improving patients' outcomes with drugs that prime their immune system to respond to checkpoint inhibition. Because the T cells' preexisting tumor recognition and the subsequent effector T-cell responses were shown to impact patients' outcomes, the authors wrote that "therapies targeted at overcoming further immune checkpoints may have relatively diminished clinical returns compared with those improving antigen presentation and priming."

Since certain patients' T cells are likely failing to activate the immune system and preventing immune checkpoint inhibitors from working as well as they could, "mechanisms to enhance baseline immune responses will be vital in improving sensitivity to [immune checkpoint blockade]," they wrote.

Watson and colleagues acknowledged that other factors beyond the tumor immune environment, such as germline genetic characteristics, could also impact checkpoint inhibitor response. They urged greater exploration of these factors and tumor-reactive clones over longer periods of time.

While the Science Immunology paper focused on metastatic melanoma, the analysis builds on similar findings in other cancer types including non-small cell lung cancer, and further supports the idea that peripheral blood samples taken at baseline and after initial immune checkpoint inhibitor treatment could provide valuable predictive and prognostic information.

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