Title | Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Lin H, Wei S, Hurt EM, Green MD, Zhao L, Vatan L, Szeliga W, Herbst R, Harms PW, Fecher LA, Vats P, Chinnaiyan AM, Lao CD, Lawrence TS, Wicha M, Hamanishi J, Mandai M, Kryczek I, Zou W |
Journal | J Clin Invest |
Volume | 128 |
Issue | 2 |
Pagination | 805-815 |
Date Published | 2018 Feb 01 |
ISSN | 1558-8238 |
Abstract | Programmed death-1 receptor (PD-L1, B7-H1) and programmed cell death protein 1 (PD-1) pathway blockade is a promising therapy for treating cancer. However, the mechanistic contribution of host and tumor PD-L1 and PD-1 signaling to the therapeutic efficacy of PD-L1 and PD-1 blockade remains elusive. Here, we evaluated 3 tumor-bearing mouse models that differ in their sensitivity to PD-L1 blockade and demonstrated a loss of therapeutic efficacy of PD-L1 blockade in immunodeficient mice and in PD-L1- and PD-1-deficient mice. In contrast, neither knockout nor overexpression of PD-L1 in tumor cells had an effect on PD-L1 blockade efficacy. Human and murine studies showed high levels of functional PD-L1 expression in dendritic cells and macrophages in the tumor microenvironments and draining lymph nodes. Additionally, expression of PD-L1 on dendritic cells and macrophages in ovarian cancer and melanoma patients correlated with the efficacy of treatment with either anti-PD-1 alone or in combination with anti-CTLA-4. Thus, PD-L1-expressing dendritic cells and macrophages may mechanistically shape and therapeutically predict clinical efficacy of PD-L1/PD-1 blockade. |
DOI | 10.1172/JCI96113 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 29337305 |
PubMed Central ID | PMC5785251 |
Grant List | R01 CA217510 / CA / NCI NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:13pm