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Cancer Immunol Res. 2017 Oct;5(10):908-919. doi: 10.1158/2326-6066.CIR-17-0016. Epub 2017 Aug 29.

The Antitumor Effects of Vaccine-Activated CD8+ T Cells Associate with Weak TCR Signaling and Induction of Stem-Like Memory T Cells.

Author information

1
Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia.
2
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
3
Division of Laboratory Medicine of Zhujiang Hospital, Southern Medical University, Guangzhou, China.
4
Department of Surgery, Medical College of Georgia, Augusta University, Augusta, Georgia.
5
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
6
Division of Laboratory Medicine of Zhujiang Hospital, Southern Medical University, Guangzhou, China. yhe@augusta.edu zfzn2013@126.com.
7
Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia. yhe@augusta.edu zfzn2013@126.com.
8
Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia.

Abstract

To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein-specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet212 and Tet499 cells correlated with their activation and differentiation states. Compared with Tet212, the population of Tet499 cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo The TCR signaling strength on Tet499 was weaker than Tet212, correlating with more severe Tet499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet499 reactivation requires a high antigen dose. Weak TCR signaling of Tet499 cells in the effector stage will also protect them from exhaustion and apoptosis when they reencounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8+ T cells, including Tscm, capable of surviving antigen restimulation to generate antitumor effects. Cancer Immunol Res; 5(10); 908-19. ©2017 AACR.

PMID:
28851693
PMCID:
PMC5626646
DOI:
10.1158/2326-6066.CIR-17-0016
[Indexed for MEDLINE]
Free PMC Article

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