Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1.

Publication Title

J Immunother Cancer

Authors

Zhi-Fa Wen
Hongxiang Liu
Rong Gao
Meng Zhou
Jie Ma
Yue Zhang
Jinjin Zhao
Yongqiang Chen
Tianyu Zhang
Fang Huang
Ning Pan
Jinping Zhang
Bernard A Fox, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 2N81 North Pavilion, 4805 N.E. Glisan St, Portland, OR, 97213, USA.Follow
Hong-Ming Hu, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, 2N81 North Pavilion, 4805 N.E. Glisan St, Portland, OR, 97213, USA.Follow
Li-Xin Wang

Document Type

Article

Publication Date

12-18-2018

Keywords

IL-10; MyD88; PD-L1; T cell; TAMs; Tumor cell-released autophagosomes (TRAPs); Tumor microenvironment

Abstract

BACKGROUND: Tumor-associated macrophages (TAMs) facilitate tumor progression via establishment of an immunosuppressive tumor microenvironment (TME). However, it is poorly understood how tumor cells could functionally modulate TAMs. Our previous work indicated that tumor cell-released autophagosomes (TRAPs), a type of LC3-II

METHODS: TRAPs isolated from multiple murine tumor cell lines and pleural effusions or ascites of cancer patients were incubated with bone marrow-derived macrophages (BMDMs) and monocytes, respectively. Cellular phenotypes were examined by flow cytometry, ELISA and quantitative PCR. TRAPs treated BMDMs were tested for the ability to suppress T-cell proliferation in vitro, and for promotion of tumor growth in vivo. Transwell chamber and neutralization antibodies were added to ascertain the inhibitory molecules expressed on BMDMs exposed to TRAPs. Knockout mice were used to identify the receptors responsible for TRAPs-induced BMDMs polarization and the signaling mechanism was examined by western blot. Autophagy-deficient tumors were profiled for phenotypic changes of TAMs and IFN-γ secretion of T cells by flow cytometry. The phenotype of monocytes from pleural effusions or ascites of cancer patients was assessed by flow cytometry.

RESULTS: TRAPs converted macrophages into an immunosuppressive M2-like phenotype characterized by the expression of PD-L1 and IL-10. These macrophages inhibited the proliferation of both CD4

CONCLUSIONS: These findings suggest the TRAPs-PD-L1 axis as a major driver of immunosuppression in the TME by eliciting macrophage polarization towards an M2-like phenotype, and highlight the potential novel therapeutic approach of simultaneously targeting autophagy and PD-L1.

Area of Special Interest

Cancer

Specialty/Research Institute

Oncology

Specialty/Research Institute

Earle A. Chiles Research Institute