A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1

Shin Foong Ngiow, Arabella Young, Nicolas Jacquelot, Takahiro Yamazaki, David Enot, Laurence Zitvogel, Mark J Smyth

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 post-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 down regulation on tumor infiltrating CD8+ T cells below which the release of adaptive immune resistance is achieved. By 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 Treg 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.