Detection and characterization of a PDAC-associated circulating CD8+CD161+ non-MAIT T-cell subset in the peripheral blood
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Summary
Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal
malignancies, with a five-year survival rate of approximately 13%. The unfavorable
prognosis is largely attributable to late diagnosis, as unspecific clinical symptoms
frequently lead to medical evaluation only at advanced or metastatic disease stages, in
which curative surgical resection is usually no longer feasible. The identification of
systemic biomarkers in peripheral blood may therefore provide a decisive diagnostic time
advantage and enable minimally invasive disease monitoring.
Against this background, peripheral blood from 22 PDAC patients was analyzed for
disease-associated alterations in immune cell populations. Fifteen patients with chronic
pancreatitis served as an inflammatory control cohort, alongside 20 healthy donors.
High-dimensional spectral flow cytometry was initially applied to characterize major T-
cell subsets. The most prominent population, CD8⁺CD161⁺ T-cells, was subsequently
sorted from 7 PDAC patients and 5 healthy donors and further investigated using single-
cell RNA sequencing complemented by histological and serological analyses.
Already at the flow cytometric level, a marked reduction of circulating CD8⁺CD161⁺ T-
cells was observed in PDAC patients. Meta-clustering analyses demonstrated, however,
that this finding primarily reflected a redistribution within the compartment rather than a
uniform loss: while mucosal-associated invariant T-cells (MAIT) were reduced, a relative
expansion of a CD8⁺CD161⁺ non-MAIT population was detected. Transcriptomic
analyses revealed that, compared with MAIT-like subsets, these cells exhibited stronger
similarity to cytotoxic, TCR-activated, tumor-reactive, as well as effector-memory– and
exhaustion-associated CD8⁺ T-cell states. In addition, circulating CD8⁺CD161⁺ T-cells in
PDAC showed increased expression of tissue-associated transcriptional programs, most
prominently within the memory-like non-MAIT population.
Consistent with these findings, CD8⁺CD161⁺ T-cells were significantly enriched in tumor
tissue, where higher intratumoral cell densities were associated with improved overall
survival. Tumor infiltration was predominantly mediated by T-BET⁺RORγt⁻ non-MAIT
cells, whereas MAIT-like populations were less frequent. Finally, systemic cytokine
signals were examined as potential modulators of subset balance. In PDAC, IL-12
correlated positively with the memory-like non-MAIT CD8⁺CD161⁺ population and
inversely with MAIT-like cells, whereas IL-18 showed the opposite association.
In summary, this work identifies a pronounced alteration within the CD8⁺CD161⁺ T-cell
compartment in the peripheral blood of PDAC patients. While MAIT-like fractions are reduced, a non-MAIT, effector-memory–like and activated CD8⁺CD161⁺ subset is
enriched and exhibits transcriptional parallels to tumor-specific activation, cytotoxicity,
and residency. These findings suggest that tumor-associated CD8⁺ T-cell states in
PDAC are not restricted to the tumor microenvironment but can also be detected
systemically and are influenced by the circulating cytokine milieu. Functional validation
studies as well as investigations in larger longitudinal cohorts will be required to assess
the potential clinical relevance of these observations and to enable the future
development of therapeutic strategies building upon these findings.
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Except where otherwise noted, this item's license is described as Attribution 4.0 International