Addressing inconsistencies about PD-L1 function on TAMs in human breast cancer (BC), Wang and Guo et al. used scRNAseq and functional and spatial cell–cell analyses to compare PD-L1+ TAMs with PD-L1- TAMs. PD-L1+ TAMs were immunostimulatory to T cells (mature and pro-inflammatory), and showed a preference for colocalizing with T cells. In contrast, PD-L1- TAMs were immunosuppressive (anti-inflammatory and pro-tumor) and interacted more frequently with cancer cells. In two independent cohorts of BC patients, those with PD-L1+/high TAMs had significantly better relapse free survival, while PD-L1-/low patients had worse clinical outcomes.
Contributed by Katherine Turner
ABSTRACT: Tumor-associated macrophages (TAMs) are the predominant cells that express programmed cell death ligand 1 (PD-L1) within human tumors in addition to cancer cells, and PD-L1(+) TAMs are generally thought to be immunosuppressive within the tumor immune microenvironment (TIME). Using single-cell transcriptomic and spatial multiplex immunofluorescence analyses, we show that PD-L1(+) TAMs are mature and immunostimulatory with spatial preference to T cells. In contrast, PD-L1(-) TAMs are immunosuppressive and spatially co-localize with cancer cells. Either higher density of PD-L1(+) TAMs alone or ratio of PD-L1(+)/PD-L1(-) TAMs correlate with favorable clinical outcome in two independent cohorts of patients with breast cancer. Mechanistically, we show that PD-L1 is upregulated during the monocyte-to-macrophage maturation and differentiation process and does not require external IFN-_ stimulus. Functionally, PD-L1(+) TAMs are more mature/activated and promote CD8(+) T cells proliferation and cytotoxic capacity. Together, our findings reveal insights into the immunological significance of PD-L1 within the TIME.
Author Info: (1) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. Electronic address: lei.wang@szu.edu.cn. (2) Department of Immuno-Oncology,
Author Info: (1) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. Electronic address: lei.wang@szu.edu.cn. (2) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (3) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. (4) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. (5) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (6) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (7) Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. (8) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. (9) International Cancer Center, Shenzhen University Medical School, Shenzhen, Guangdong 518055, China. (10) Department of Thyroid and Breast Surgery, Shenzhen Second People's Hospital/First Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong 518035, China. (11) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (12) Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (13) Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. (14) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address: plee@coh.org.
