Understanding why some patients do not respond to cancer therapy, such as anti-PD-1 therapy, requires greater knowledge of the different cellular populations making up the immune system and particularly those populations that are responding at the site of the tumor. CD8+ cytotoxic T cells can recognize and eliminate cancer cells, but cancer cells can escape their immune surveillance by various molecular mechanisms, which can lead to CD8+ T cell exhaustion and dysfunction. These dysfunctional CD8+ T cells are known to express PD-1. However, CD8+ T cells are only a subset of the diverse T cell population and many of these T cells from other subsets have yet to be fully characterized.
Using next-generation sequencing (NGS) technology, Dr. Ming Li and their team discovered a population of innate-like T cells (ILTCKs) that possess high cytotoxic function and are resistant to exhaustion.1 Unlike conventional CD8+ T cells, ILTCKs do not undergo clonal expansion or differentiation after activation to the same extent as conventional CD8+PD-1+ T cells. Furthermore, ILTCKs’ cytolytic phenotype and broad reactivity are more similar to the function of an innate immune response. Dr. Ming and colleagues discovered that, unlike conventional CD8+ PD-1+ T cells, ILTCKs suppressed tumor growth upon exposure to IL-15 derived from cancer cells.
The discovery of ILTCKs
Using a murine model of breast cancer, a diverse population of tumor-infiltrating T cells (CD45+TCRβ+CD8α+ T cells) were selected for transcriptomic analysis via single-cell RNA sequencing. Five different clusters of CD8+ T cell populations were found. The clustering of the different populations was based on the following:
- Highly expressed naïve T cell markers
- Highly expressed T cell dysfunction markers (including PD-1)
- Highly expressed genes encoding the natural killer cell receptor and the αβ T cell receptor (αβILTCKs)
- Highly expressed type 1 interferon stimulated genes
- Upregulation of genes indicative of a proliferative state
Further analysis of these separate clusters discovered that αβILTCKs were distinctly segregated from exhausted T cells expressing dysfunction markers (e.g. PD-1+ T cells).
Characterizing the distinction between αβILTCKs and PD-1+ T cells
Using single-cell TCR sequencing (iRepertoire’s iPair methodology), Ming and colleagues compared the paired TCR sequences found on PD-1+ T cells and αβILTCKs. While most PD-1+ T cells shared five unique TCR pairs that resulted from clonal expansion, receptors on αβILTCKs were polyclonal and therefore suggest only modest levels of clonal expansion. Furthermore, there was no overlap of TCR pairs found in both populations. Therefore, these two cell populations were derived from different precursor cells. When assessing the specificity of the two subset populations, only αβILTCK TCRs were reactive to heterologous cancer cells, which suggests their ability to recognize similar unmutated antigens of cancer cells derived from different mice.
How are αβILTCKs involved in immunosurveillance?
αβILTCKs expressing FCER1G responded to cancer-cell-derived IL-15 and suppressed tumor growth. This discovery uncovers a potential to exploit IL-15 signaling to activate αβILTCK cytotoxicity against tumor cells. The upregulated expression of FCER1G among αβILTCKs was observed within different cancer tissues, which indicates it as a marker for cells in the αβILTCK lineage regardless of the cell’s activation state. However, signals from the microenvironment may still control or limit the expansion of αβILTCKs and therefore more studies are required to fully characterize the activation of αβILTCKs.
In summary, Dr. Li and colleagues characterized the αβILTCK population and the potential for these cells to contribute to cancer immunosurveillance. The αβILTCKs are distinct from the conventional CD8+ T cells but also participate in tumor-elicited immune response. This research underlines the importance of characterizing the diverse cellular populations that may be useful in suppressing cancer growth. The characterization of the TCR VDJ pairs were made possible with iRepertoire’s arm-PCR technology and iPair.
Read the full study here: https://pubmed.ncbi.nlm.nih.gov/35444279/
Chou, C. et al. Programme of self-reactive innate-like T cell-mediated cancer immunity. Nature 1–7 (2022) doi:10.1038/s41586-022-04632-1.