NEW YORK – Immune cell gene expression patterns and subtypes may hold clues to immune-related adverse effects (AEs) that cancer patients develop after immune checkpoint blockade immunotherapy (ICI), new research suggests.
As investigators reported in Cell Reports Medicine on Monday, they used single-cell RNA sequencing to profile circulating T cells in pre-treatment peripheral blood samples from two dozen individuals undergoing anti-PD-1, anti-PD-L1, or anti-CTLA-4 immunotherapy cancer treatment, including 18 lung adenocarcinoma patients. They identified gene expression patterns and T-cell subgroups that corresponded to grade 2 or grade 3 immune-related adverse events (irAEs) after four to six weeks of treatment.
"irAEs are associated with significant morbidity and, in some cases, lifelong disability," senior and corresponding author Adam Mor, a researcher at Columbia University Medical Center, and his colleagues explained, noting that "we discovered correlations between the presence of specific subsets of T cells at baseline and the development of arthritis, pneumonitis, and thyroiditis AEs."
By taking the brakes off immune checkpoints, ICI treatments can lead to excessive T-cell activation, prompting acute and chronic inflammatory events that can affect a range of tissue and organ types in patients. Even so, the team explained, the individual contributors to such irAEs have not been fully understood so far.
"Patients who have a prior history of autoimmune disease are thought to be at increased risk for developing irAEs," the authors explained, "but aside from this, no predictive factors have been identified to guide patients [about] their individual risk of toxicity with ICI treatment, a major unmet need in clinical decision-making."
Using a strategy called "cellular indexing of transcriptomes and epitopes sequencing" (CITE-seq), the team generated and analyzed pre-treatment scRNA-seq profiles from all 24 patients, along with post-treatment samples from 15 patients who developed irAEs. That led to T-cell signatures and clusters not found in patients who did not develop irAEs over a year of follow-up, along with expression patterns and T-cell subtypes found prior to treatment that appeared to predict specific side effects.
Among other expression signatures and cell clusters, the researchers saw ties between reduced representation of a pre-treatment CD8 central memory (CM) cell cluster and risk of developing inflammatory arthritis after ICI, for example. They also linked post-ICI arthritis risk to reduced baseline levels of TCF7-expressing T helper 2 (TH2) cells.
On the other hand, enhanced levels of CCR7-expressing CD4 TH2 cells and KLF6- and JUN-positive TH2 cells appeared to coincide with risk of pneumonitis, while immune-associated thyroiditis after ICI corresponded to higher-than-usual levels of CD4 TH17 cells, including CD4 TH17 cells expressing the RORC transcription factor coding gene and interleukin-21 before treatment.
"These data support the hypothesis that different populations of T cells are associated with different irAEs and that characterization of these cells' pre-treatment has the potential to serve as a toxicity-specific predictive biomarker," the authors wrote, noting that they ultimately hope to bring the findings to the clinic.
"Through our ongoing efforts, we will translate our findings to the clinic by developing a personalized flow cytometry- and RT-PCR-based tool to prove the premise that quantification of these populations of cells could accurately predict irAEs," they explained, "altogether enabling many more patients with cancer to safely receive immunotherapies."