NEW YORK – By systematically profiling T-cell receptor (TCR) patterns and tumor-infiltrating lymphocyte (TIL) antigen recognition repertoires in the tumor microenvironment of pediatric brain cancers, a University of Pittsburgh-led team has identified T-cell features with apparent ties to survival that may eventually serve as prognostic markers or treatment clues in children with often-deadly brain tumors.
The findings appeared in Science Translational Medicine on Wednesday.
"This study is part of our laboratory's overall research focused on the urgent need of identifying new feasible, safe, and effective immunotherapies for kids with brain tumors," senior author Gary Kohanbash, a neurological surgery researcher affiliated with the UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh, said in an email.
For their study, Kohanbash and colleagues in the US, Canada, Switzerland, and Israel got a look at TCR repertoires across pediatric brain cancer types by analyzing TCR alpha (TRA)- and TCR beta (TRB) gene expression with bulk RNA sequences spanning 15 major pediatric tumor histology types. They also assessed RNA-seq profiles representing peripheral blood mononuclear cell samples from 730 healthy children.
With these data, the team was able to dig into TCR composition and diversity within and across pediatric brain tumor types, highlighting TCR clonotypes recognizing tumor-associated antigens and tumor-specific antigens, or neoantigens, linked to mutations within the tumors.
"[O]ur research delves into the functional aspect of T-cell responses by examining clonal expansion via T-cell receptor (TCR) recombination," Kohanbash explained. "This method provides a direct measure of T-cell proliferation and activation, surpassing the limitations of gene expression or histological analyses."
In particular, the investigators teased out T-cell activation and expansion patterns that they dubbed the "clonal expansion-activation index" (CEI) — a metric that appeared to provide prognostic insights in the pediatric brain cancer cases.
"We show that a transcriptomic-based metric of T-cell clonality, which may imply tumor antigen-related T-cell activation and expansion, is associated with prognosis across tumor entities and subtypes," the authors reported.
While enhanced T-cell clonality and limited TCR clonotype diversity tended to track with more favorable survival outcomes, for example, the team saw ties between low CEI and relatively poor survival outcomes, suggesting T-cell clonality may provide additional information for clinicians.
"Currently, tumor classifications are largely based on histologic and molecular features of the tumors," Kohanbash noted. "We believe it is possible that quantifying clonal expansion of T cells for each patient's tumor may ultimately be an important addition to tumor classifications and inform clinicians in deciding how to best guide treatment for patients and monitor the effects of therapies, especially for immunotherapies."
The team got a closer look at the relationship between CEI and T-cell activation and clonal expansion with follow-up experiments on five diffuse intrinsic pontine glioma, three ependymoma, and three low-grade glioma tumors, which were characterized with the help of single-cell RNA-seq and TCR-seq.
Beyond the potential implications for managing pediatric brain cancer cases, the researchers noted that the new findings may provide insights needed to come up with novel strategies to treat various pediatric brain tumor types based on immune features found in the tumor microenvironment, particularly for predicting tumor antigen production based on TCR features found in the tumor microenvironment.
"[I]dentification of the most promising targets remains one of the greatest challenges for personalized antigen-based immunotherapies," Kohanbash explained. "Our antigen discovery pipeline, while still early in development, has potential to find these promising antigens and to be continuously improved upon through the addition of new data as they become available."
In addition to efforts aimed at validating their current findings in larger datasets encompassing still other pediatric brain tumor subtypes, he noted that members of the team are currently considering translational strategies for bringing the results to the clinic — from TCR-engineered T cells targeting antigens identified to tailored tumor-antigen immunotherapies informed by infiltrating T-cell-based antigen predictions.