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.
Highlights
Cancer immunotherapy has revolutionized therapeutic strategies in clinical oncology over the last decade
3.2 The Frequency of CD71+ Erythroid Progenitor Cells Reduced While CD8+ T Cells Increased Significantly in the Advanced Lewis Lung Cancer Mouse Model After Ultrasound-Targeted Microbubble Destruction Treatment
Our study originally presented ultrasound-targeted microbubble destruction (UTMD) to modulate the immunity outside tumor microenvironment (TME) by targeting the immunosuppressive splenic CD71+ erythroid progenitor cells (CECs)
Summary
Cancer immunotherapy has revolutionized therapeutic strategies in clinical oncology over the last decade. The systemic immunity in cancer beyond the TME is essential for effective immune response toward immunotherapy, and the tumor immune macroenvironment is remarkably plastic [2,3,4]. The spleen size increase was mainly attributed to CECs [14] It suppresses the immune response by inhibiting the production of interferon-g (IFN-g) via soluble cytokines such as TGF-b. CEC modulates T cells through direct cell–cell interaction via PDL-1/PD-1 pathway and expresses genes encoding immune checkpoint molecules [15], so we assume that the absence of CEC increases the production of immunomodulated cytokines and could act as a checkpoint blockade, and the immune checkpoint inhibitors may partially diminish the tumor-promoting effects of CECs as well. CECs could be a new target to restore peripheral immune perturbation in cancer and enhance immunotherapy’s efficiency to inhibit tumor growth
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