Maria Lozano-Rabella, PhD
CHUV/UNIL/Ludwig Institute for Cancer Research
"Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL-ACT) is a promising personalized cancer treatment but requires invasive tumor biopsies to isolate effector cells. As TILs can circulate between tumors, lymph nodes and blood, circulating TILs (cTIL) may serve as an accessible surrogate. Liquid biopsies could enable characterization of TIL repertoires and facilitate identification of tumor-reactive (TR) T-cell receptors (TCRs).
We aimed to 1) assess TCR repertoire overlap between tumor and blood, 2) characterize TIL circulation dynamics, and 3) define a proteo-transcriptomic signature of circulating TR T cells (cTRT). Matched tumor and blood samples were collected from seven metastatic melanoma patients with distinct clinical outcomes to TIL-ACT. Single-cell RNA/TCR sequencing and CITE-seq were performed. Clonotypes were classified as blood-exclusive, tumor-exclusive or shared, and tumor reactivity was assigned using experimentally validated data.
Clinical benefit to TIL therapy was associated with higher CD8⁺ T-cell richness and clonality in tumors, but not in blood, and responders showed higher cTIL fractions. Although TR clonotypes were predominantly retained in tumors, cTRT were less exhausted than tumor-resident counterparts. They also displayed transcriptomic and proteomic features supporting an actionable TR blood signature.
These findings support cTIL as a minimally invasive source of TR T cells with potential for biomarker discovery and TCR-based therapies."
We aimed to 1) assess TCR repertoire overlap between tumor and blood, 2) characterize TIL circulation dynamics, and 3) define a proteo-transcriptomic signature of circulating TR T cells (cTRT). Matched tumor and blood samples were collected from seven metastatic melanoma patients with distinct clinical outcomes to TIL-ACT. Single-cell RNA/TCR sequencing and CITE-seq were performed. Clonotypes were classified as blood-exclusive, tumor-exclusive or shared, and tumor reactivity was assigned using experimentally validated data.
Clinical benefit to TIL therapy was associated with higher CD8⁺ T-cell richness and clonality in tumors, but not in blood, and responders showed higher cTIL fractions. Although TR clonotypes were predominantly retained in tumors, cTRT were less exhausted than tumor-resident counterparts. They also displayed transcriptomic and proteomic features supporting an actionable TR blood signature.
These findings support cTIL as a minimally invasive source of TR T cells with potential for biomarker discovery and TCR-based therapies."
