The complex landscape of cytotoxic T lymphocytes (CTLs)
image: Diferentiation trajectories of CTLs of thymic developmental origins and in the peripheral blood.
Credit: This fgure was created based on the tools provided by Biorender.com
Cancer immunotherapy has revolutionized treatment for many patients, but significant challenges remain in predicting who will respond to these life-saving treatments. A new comprehensive review published in Molecular Cancer sheds light on why some patients benefit from immunotherapy while others do not, focusing on the remarkable diversity of cytotoxic T lymphocytes (CTLs) - the immune system's primary cancer-fighting cells2.
"CTLs are not a uniform population of cells," explains Dr. Peng Luo, one of the study's corresponding authors from Southern Medical University. "We now understand that CTLs encompass diverse subsets including not only classical CD8+ T cells, but also CD4+ CTLs, γδ-CTLs, and invariant natural killer T cells, each with unique mechanisms for recognizing and eliminating cancer cells."
The research team systematically analyzed current knowledge about CTL subsets, their identifying biomarkers, and the molecular pathways controlling their development and function. One of the most significant findings relates to the challenge of accurately identifying these cells. "A major problem we've identified is that lymphocytes expressing molecules associated with cytotoxicity don't necessarily exhibit actual cytotoxic function," notes Dr. Quan Cheng from Central South University. "This has important implications for how we assess immune responses in cancer patients."
The study reveals that different CTL subsets utilize distinct killing mechanisms. While CD8+ CTLs primarily use the well-known perforin/granzyme pathway, CD4+ CTLs can develop from various helper T cell subpopulations and employ both direct killing mechanisms and indirect tumor elimination through immune cell activation2. γδ T cells, found mainly in barrier tissues, can rapidly respond to threats and show promise for cancer immunotherapy applications.
Perhaps most intriguingly, the research highlights how tumor environments shape CTL behavior through a process called plasticity. "Cancer cells don't remain static - they evolve and adapt, and our immune cells must adapt in response," explains Dr. Yifeng Bai from the University of Electronic Science and Technology of China. "Understanding this dynamic interaction is crucial for developing more effective immunotherapies."
The review identifies several key transcription factors that control CTL development, including T-bet, Blimp-1, and RUNX3, which could serve as targets for enhancing immune responses. The team also describes how epigenetic modifications - changes in gene expression that don't alter DNA sequence - play important but poorly understood roles in CTL regulation2.
Looking forward, the researchers outline critical questions that need addressing: refining how we define and identify CTLs, characterizing their diverse subtypes, understanding their interactions with the tumor microenvironment, and developing multi-omics approaches to better profile these cells. "Answering these questions will be essential for optimizing CTL-based immunotherapies and improving outcomes for cancer patients," the authors conclude.