In:
Liver Cancer, S. Karger AG, Vol. 12, No. 2 ( 2023), p. 129-144
Kurzfassung:
〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Checkpoint inhibitors act on exhausted CD8 〈 sup 〉 + 〈 /sup 〉 T cells and restore their effector function in chronic infections and cancer. The underlying mechanisms of action appear to differ between different types of cancer and are not yet fully understood. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Here, we established a new orthotopic HCC model to study the effects of checkpoint blockade on exhausted CD8 〈 sup 〉 + 〈 /sup 〉 tumor-infiltrating lymphocytes (TILs). The tumors expressed endogenous levels of HA, which allowed the study of tumor-specific T cells. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 The induced tumors developed an immune-resistant TME in which few T cells were found. The few recovered CD8 〈 sup 〉 + 〈 /sup 〉 TILs were mostly terminally exhausted and expressed high levels of PD-1. PD-1/CTLA-4 blockade resulted in a strong increase in the number of CD8 〈 sup 〉 + 〈 /sup 〉 TILs expressing intermediate amounts of PD-1, also called progenitor-exhausted CD8 〈 sup 〉 + 〈 /sup 〉 TILs, while terminally exhausted CD8 〈 sup 〉 + 〈 /sup 〉 TILs were almost absent in the tumors of treated mice. Although transferred naïve tumor-specific T cells did not expand in the tumors of untreated mice, they expanded strongly after treatment and generated progenitor-exhausted but not terminally exhausted CD8 〈 sup 〉 + 〈 /sup 〉 TILs. Unexpectedly, progenitor-exhausted CD8 〈 sup 〉 + 〈 /sup 〉 TILs mediated the antitumor response after treatment with minimal changes in their transcriptional profile. 〈 b 〉 〈 i 〉 Conclusion: 〈 /i 〉 〈 /b 〉 In our model, few doses of checkpoint inhibitors during the priming of transferred CD8 〈 sup 〉 + 〈 /sup 〉 tumor-specific T cells were sufficient to induce tumor remission. Therefore, PD-1/CTLA-4 blockade has an ameliorative effect on the expansion of recently primed CD8 〈 sup 〉 + 〈 /sup 〉 T cells while preventing their development into terminally exhausted CD8 〈 sup 〉 + 〈 /sup 〉 TILs in the TME. This finding could have important implications for future T-cell therapies.
Materialart:
Online-Ressource
ISSN:
2235-1795
,
1664-5553
Sprache:
Englisch
Verlag:
S. Karger AG
Publikationsdatum:
2023
ZDB Id:
2666925-0
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