One reason that adoptive cell transfer has met with limited clinical success is that approaches based on this strategy have not fully taken into account the role of the tumor microenvironment as a limiting factor in immunotherapy. Recently reported studies by Peng and colleagues1 from The University of Texas MD Anderson Cancer Center in Houston and Juntendo University School of Medicine in Tokyo, Japan, indicate that blockade of the immunosuppressive receptor programmed cell death (PD)-1 on transferred T cells increases T-cell migration to tumors and enhances the activity of adoptive cell transfer.
The investigators found that in a murine model of adoptive cell transfer, PD-1 expressed on transferred T cells at the tumor site was upregulated compared with expression on transferred T cells in the peripheral blood or spleen. Since PD-1 can attenuate T-cell–mediated antitumor activity, the investigators tested whether use of an anti–PD-1 antibody could enhance activity of adoptive cell transfer. Concomitant adoptive cell transfer and administration of anti–PD-1 antibody increased the number of transferred T cells at the tumor site and resulted in greater tumor regression compared with either treatment alone.
Although anti-PD-1 antibody did not reduce levels of immunosuppressive regulatory T cells or myeloid-derived suppressor cells, it was associated with increased expression of IFN-γ and the IFN-γ inducible chemokine CXCL10 in the tumor. Bone marrow transplant experiments in IFN-γ receptor knockout mice showed that IFN-γ was crucial in controlling T cell tumor infiltration mediated by PD-1.
As concluded by the investigators, “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.” ■
1. Peng W, Liu C, Xu C, et al: PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res 72:5209-5218, 2012.