PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines.
Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements, many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor programmed cell death-1 (PD-1) expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. As PD-1 can attenuate T-cell-mediated antitumor responses, we tested whether its blockade with an anti-PD-1 antibody could enhance the antitumor activity of ACT in this model. Cotreatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared with treatments with either agent alone. While anti-PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow-transplant experiments using IFN-γR-/- mice implicated IFN-γ as a crucial nexus for controlling PD-1-mediated tumor infiltration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites.
Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Weiyi
W
Peng
Chengwen
C
Liu
Chunyu
C
Xu
Yanyan
Y
Lou
Jieqing
J
Chen
Yan
Y
Yang
Hideo
H
Yagita
Willem W
WW
Overwijk
Gregory
G
Lizée
Laszlo
L
Radvanyi
Patrick
P
Hwu
D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D018925:Chemokines / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D015854:Up-Regulation
D018925:Chemokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma