Ultrasound-Targeted Microbubble Destruction Alleviates Immunosuppression Induced by CD71+ Erythroid Progenitor Cells and Promotes PDL-1 Blockade Immunotherapy in the Lewis Lung Cancer Model

Abstract

The CD71+ erythroid progenitor cells (CECs) exhibit distinctive immunosuppressive properties and regulate antitumor immunity to enable tumor growth. We presented a novel and non-invasive approach to improving immunity by targeting the splenic CECs via sonoporation generated by ultrasound-targeted microbubble destruction (UTMD). The systematic immunity enhanced by the reduction of PDL-1-expressing CECs also benefits the PDL-1 blockade therapy. In the Lewis lung cancer (LLC) model, the study group was treated by UTMD for 10 min at the splenic area with or without anti-mouse PDL-1 intraperitoneal injection. The frequency of splenic CEC, lymphocyte, and cytokine production was analyzed by flow cytometry. Serum interleukin-2 (IL-2) was tested by ELISA. Tumor volume was evaluated by two-dimensional ultrasound. The UTMD treatment consisted of ultrasound sonication and Sonazoid™ microbubble injection through the caudal vein. The mechanic index (MI) of ultrasound was set between 0.98 and 1.03. The results showed a significant reduction of splenic CECs and increased frequency of CD8+ T cells treated by UTMD treatment in the late-stage tumor. Tumor growth could be inhibited by UTMD combined with PDL-1 blockade therapy. The frequencies of interferon-γ (IFN-γ) producing CD8+ and CD4+ T cells were significantly increased after being treated by the combination of UTMD and PDL-1 blockade, while the reactive oxygen species (ROS) production and the fraction of the TGF-β-producing CD11b+ cells were significantly decreased. These preliminary findings suggest that UTMD enhances immune response and facilitates PDL-1 blockade therapy by targeting immunosuppressive CECs in the spleen. Our study provides new aspects and possibilities for treating cancer-related infection and tumor control in oncology.

Ultrasound-targeted microbubble destruction remodels tumour microenvironment to improve immunotherapeutic effect

“…2c ). Similarly, one recent study elucidated that UTMD decreased the frequency of CD71 + erythroid progenitor cells, which suppress the immune response [ 74 ] (Fig. 2d ).…”

“…UTMD with pIFN-β and anti-PD-1 also slowed tumour growth by 4-fold and even showed complete tumour regression by enhancing T-cell recruitment in a mouse model of breast cancer [ 51 ]. For the Lewis lung cancer (LLC) model, UTMD and anti-PD-L1 combination therapy induced an increase in IFN-γ production, causing an increase in CD8 + T-cell frequency to inhibit LLC progression [ 74 ]. Moreover, researchers constructed TLR agonist (R837)-loaded pH-responsive liposomes (PEOz-Lip@R837) to treat pancreatic cancer.…”

“…It also demonstrates substantial prospects for clinical application. First, UTMD is safe and harmless to the heart, spleen, kidneys and other organs [ 74 , 92 ]. Studies have shown that UTMD did not cause significant weight loss or a decrease in cellular activity in experimental animals [ 116 , 139 ].…”

Targeted Nanobubbles of PD-L1 mAb Combined with Doxorubicin as a Synergistic Tumor Repressor in Hepatocarcinoma

“… 41 Ultrasound targeted microbubble destruction combined with PD-L1 blockade can promote the activation and differentiation of CD8+ T cells, increase IFN-γ secretion, reverse an immunosuppressive microenvironment, enhance acquired immunity, and inhibit tumor growth. 42 Kim et al 43 developed a PD-L1 targeted immune microbubble complex that can not only reduce the immune-related toxicity induced by antibodies but also improve the therapeutic efficacy when combined with focused ultrasound. In addition, Li et al 44 found that the ultrasound stimulation of microbubble cavitation could promote tumor blood perfusion, enhance CD8+ T cell infiltration, and PD-L1 antibody delivery, thereby increasing the number and activity of CD8+ T cells and thus generating strong antitumor effects.…”

Cavitation-Mediated Immunomodulation and Its Use with Checkpoint Inhibitors

“…Tan et al [49] Spleens of LLC tumour-bearing mice were in the first study divided into two groups: (1) US+CA and (2) untreated. The CAs were Sonazoid MBs.…”