A threshold level of intratumor CD8<sup>+</sup> T-cell PD1 expression dictates therapeutic response to anti-PD1

Ngiow, Shin Foong, Young, Arabella, Jacquelot, Nicolas, Yamazaki, Takahiro, Enot, David, Zitvogel, Laurence and Smyth, Mark J. (2015) A threshold level of intratumor CD8<sup>+</sup> T-cell PD1 expression dictates therapeutic response to anti-PD1. Cancer Research, 75 18: 3800-3811. doi:10.1158/0008-5472.CAN-15-1082


Author Ngiow, Shin Foong
Young, Arabella
Jacquelot, Nicolas
Yamazaki, Takahiro
Enot, David
Zitvogel, Laurence
Smyth, Mark J.
Title A threshold level of intratumor CD8+ T-cell PD1 expression dictates therapeutic response to anti-PD1
Journal name Cancer Research   Check publisher's open access policy
ISSN 1538-7445
0008-5472
Publication date 2015-09-15
Year available 2015
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-15-1082
Open Access Status Not Open Access
Volume 75
Issue 18
Start page 3800
End page 3811
Total pages 12
Place of publication Philadelphia, Pennsylvania, United States
Publisher American Association for Cancer Research
Language eng
Formatted abstract
Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1lo), myeloid, and T-cell PDL1 (PDL1hi) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8+ T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8+ T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1hi T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1lo immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1–resistant tumors and PD1hi CD8+ T cells. Our analyses provide a framework to interrogate intratumor CD8+ T-cell PD1 and immune PDL1 levels and response in human cancer.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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