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.
CITATION STYLE
Ngiow, S. F., Young, A., Jacquelot, N., Yamazaki, T., Enot, D., Zitvogel, L., & Smyth, M. J. (2015). A threshold level of intratumor CD8+ T-cell PD1 expression dictates therapeutic response to anti-PD1. Cancer Research, 75(18), 3800–3811. https://doi.org/10.1158/0008-5472.CAN-15-1082
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