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Transcriptome Sequencing and T-Cell Receptor Spatial Mapping in Renal Cell Carcinoma

By: Vanessa A. Carter, BS
Posted: Thursday, December 16, 2021

Bryan Iorgulescu, MD, FCAP, of the Dana-Farber Cancer Institute, Boston, and colleagues developed Slide T-cell receptor (TCR) sequencing to sequence whole transcriptomes and T-cell receptors and apply it to immune checkpoint inhibitor–treated renal cell carcinoma. Their results, presented during the 2021 Society for Immunotherapy of Cancer (SITC) Annual Meeting (Abstract 76), found that this process is effective at integrating spatial transcriptomics with TCR detection at a resolution of 10 µm, relating T-cell gene expression and clonality to their position within tumors.

“Our findings suggest that a clonotype’s T cells may exhibit mixed responses to immune checkpoint inhibitors depending on their spatial localization,” concluded the investigators. “The heterogeneity among clonotypes, in both gene expression and organization, underscores the importance of studying the T-cell receptor repertoire with spatial resolution.”

Slide TCR sequencing enables the amplification of segments that extend from upstream of CDR3 to the 3' end of the TCR transcript. Spleen OT-I cells were initially tested, and then this methodology was applied to samples from three patients with clear cell renal cell carcinoma.

In 37.1% of beads with Trac/Trbc2 constant sequences, TCR α/β CDR3 sequences were observed. This method was then used to analyze a clear cell renal cell carcinoma lung metastasis, in which 1,132 unique clonotypes with distinct spatial distributions were identified; eight were enriched in tumor, and five were depleted (P < .05).

T-clonotype beads were dichotomized by gene-set expression using a T-cell gene-set associated with poor response to immune checkpoint inhibitors, where spatial segregation of this gene set’s expression was found both across and within clonotypes. TCR-4 and TCR-2 displayed high expression of poor immune checkpoint inhibitor response close to the tumor edge but low expression within the tumor compartment. Notably, this was suggestive of transcriptionally distinct subpopulations of these clonotypes, which were dependent on the extent of tumor infiltration.

Disclosure: No disclosure information was provided.



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