The T cell receptor landscape of childhood brain tumors.

in Science translational medicine by Itay Raphael, Zujian Xiong, Chaim T Sneiderman, Rebecca A Raphael, Moshe Mash, Lance Schwegman, Sydney A Jackson, Casey O'Brien, Kevin J Anderson, ReidAnn E Sever, Liam D Hendrikse, Sarah R Vincze, Aaron Diaz, James Felker, Javad Nazarian, Yael Nechemia-Arbely, Baoli Hu, Udai S Kammula, Sameer Agnihotri, Jeremy N Rich, Alberto Broniscer, Jan Drappatz, Taylor J Abel, Shikhar Uttam, Eugene I Hwang, Thomas M Pearce, Michael D Taylor, Michal Nisnboym, Thomas G Forsthuber, Ian F Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash

TLDR

  • The study characterizes the T cell receptor landscape of tumor-infiltrating lymphocytes in pediatric brain tumors, identifying a T cell clonality index that informs patient prognosis and putative tumor antigens as targets for antitumor immunity.

Abstract

The diverse T cell receptor (TCR) repertoire confers the ability to recognize an almost unlimited array of antigens. Characterization of antigen specificity of tumor-infiltrating lymphocytes (TILs) is key for understanding antitumor immunity and for guiding the development of effective immunotherapies. Here, we report a large-scale comprehensive examination of the TCR landscape of TILs across the spectrum of pediatric brain tumors, the leading cause of cancer-related mortality in children. We show that a T cell clonality index can inform patient prognosis, where more clonality is associated with more favorable outcomes. Moreover, TCR similarity groups' assessment revealed patient clusters with defined human leukocyte antigen associations. Computational analysis of these clusters identified putative tumor antigens and peptides as targets for antitumor T cell immunity, which were functionally validated by T cell stimulation assays in vitro. Together, this study presents a framework for tumor antigen prediction based on in situ and in silico TIL TCR analyses. We propose that TCR-based investigations should inform tumor classification and precision immunotherapy development.

Overview

  • The study investigated the T cell receptor (TCR) landscape of tumor-infiltrating lymphocytes (TILs) in pediatric brain tumors.
  • The researchers used a T cell clonality index to estimate patient prognosis, finding that more clonal TILs were associated with better outcomes.
  • The study aimed to identify putative tumor antigens and peptides as targets for antitumor T cell immunity and develop a framework for tumor antigen prediction.

Comparative Analysis & Findings

  • The study showed that patients with more clonal TILs had better outcomes, highlighting the importance of T cell clonality in patient prognosis.
  • Computational analysis identified putative tumor antigens and peptides as targets for antitumor T cell immunity, which were functionally validated in vitro.

Implications and Future Directions

  • The study suggests that TCR-based investigations can inform tumor classification and guide precision immunotherapy development.
  • Future research can build on these findings to further explore the role of TCRs in pediatric brain tumors and develop more effective immunotherapies.
  • The framework for tumor antigen prediction developed in this study can be applied to other types of cancer to identify novel targets for T cell-based therapies.
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