Specialized regulatory T cells (Tregs) help moderate inflammation in the tumor microenvironment (TME). Unfortunately, this response also enables tumor growth. In a recently published study, Dr. Mingyong Liu and team1 utilized iRepertoire’s arm-PCR platform for T cell receptor (TCR) sequencing to understand how Tregs accumulate in tissues.
Multiple pathways may contribute to the accumulation: recruitment of circulating Tregs, expansion of the resident Treg population, or conversion of CD4+ T cells to FoxP3-expressing Tregs. By understanding how Tregs accumulate, it might be possible to design therapies that block their collection and suppression for improved cancer treatment.
Characterization of Tregs in the TME
To determine the origin of omental TME Tregs, Treg populations were sorted and TCR libraries were prepared and sequenced using iRepertoire’s arm-PCR platform and analyzed using iRepertoire’s bioinformatics pipeline. The Liu team compared the TCRβ chain CDR3 region repertoires of Tregs derived from the omenta of naïve and tumor-bearing mice to Treg clonotype CDR3 reference sequences from matching peripheral blood, thymus, and spleen. TCR profiles were expected to indicate whether Treg accumulation in the TME was driven by recruitment, local clonal expansion, or conversion of CD4+ T cells. Treg gene expression profiles were generated to capture specific Treg functional changes occurring within the TME.
The Case for Recruitment
The team discovered that tumor implantation promoted the accumulation of a diverse repertoire of Tregs. TCR sequencing revealed a TME Treg TCR repertoire that aligns with that of circulating Tregs and Tregs from the thymus and spleen suggesting that Tregs are recruited to the TME, not clonally expanded or converted resident immune cells.
TME Treg profiles specifically contained upregulated chemokine receptors CCR4 and CCR10 suggesting a recruitment pathway. Newly-arrived Tregs were found to overexpress chemokine receptors CCR1, CCR8, and CXCR6 suggesting recent movement of Tregs into the omentum. Expression profiles of recruited Tregs showed a shift in genetic activity over time that closely aligned with adipose resident Tregs, including suppression of the local immune response. Recruited Tregs appear to alter their behavior to align with the new environment. It may be possible to leverage information on Treg recruitment to develop therapies that block Treg migration or counteract Treg suppression for improved treatment outcomes.
Tools such as TCR repertoire analysis can provide insight into the origins and movements of T cells as part of the body’s defense to disease. For more information on immune profiling, read the full study here: https://doi.org/10.1158/2326-6066.CIR-21-0880
Liu, M. et al. Circulating Tregs Accumulate in Omental Tumors and Acquire Adipose-Resident Features. Cancer Immunol Res. 9 Mar 2022 doi:10.1158/2326-6066.CIR-21-0880