Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis

Hongjun Li,Tianyuan Ci,Gianpietro Dotti,Zhaowei Chen,Guojun Chen,Di Wen,Zejun Wang,Zhen Gu,Zhifeng Gu,R Bryan Bell,Jinqiang Wang,Ruoxin Li,Huan Meng

doi:10.1038/s41467-021-22674-3

Abstract

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.

Highlights

Therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death
70% of the surface-decorated anti-programmed cell death-ligand 1 (aPDL1) was released from platelets by plateletderived microparticles (PMP) after eight hours of treatment (Supplementary Fig. 3)
No increase of immune response, including numbers of CD3+, CD4+ and CD8+ T cells, was detected in the non-tumour-bearing mice treated with P@aPDL1 and Vadimezan compared with those treated with PBS

Summary

Results

Quantitative analysis showed that mice co-treated with Vadimezan and P@aPDL1 held 3- to 10-fold amount of aPDL1 in the tumour as compared to mice treated with P@aPDL1 and free aPDL1 antibody, respectively (Fig. 2c, d) These results demonstrated that combining P@aPDL1 with an antiangiogenic agent caused the accumulation of aPDL1 in the metastatic tumour, which could potentially augment the efficacy of ICB. Tumour-free survival at day 60 was 50% in mice receiving P@aPDL1 combined with Vadimezan treatment, and rare tumour lesions were observed in the lung at the time of the termination of the experiment (Fig. 3e–g). Immunofluorescence staining revealed more CD4+ and CD8+ T cells in metastatic lung tumours in mice with P@aPDL1 and Vadimezan treatment as compared to control groups (Fig. 4e and Supplementary Fig. 9).

G3 G5 G6

Discussion

Methods