Engineering PD-1-Presenting Platelets for Cancer Immunotherapy

Abstract

Radical surgery still represents the treatment choice for several malignancies. However, local and distant tumor relapses remain the major causes of treatment failure, indicating that a postsurgery consolidation treatment is necessary. Immunotherapy with checkpoint inhibitors has elicited impressive clinical responses in several types of human malignancies and may represent the ideal consolidation treatment after surgery. Here, we genetically engineered platelets from megakaryocyte (MK) progenitor cells to express the programmed cell death protein 1 (PD-1). The PD-1 platelet and its derived microparticle could accumulate within the tumor surgical wound and revert exhausted CD8 T cells, leading to the eradication of residual tumor cells. Furthermore, when a low dose of cyclophosphamide (CP) was loaded into PD-1-expressing platelets to deplete regulatory T cells (Tregs), an increased frequency of reinvigorated CD8 lymphocyte cells was observed within the postsurgery tumor microenvironment, directly preventing tumor relapse.

Advanced Nanotechnology Leading the Way to Multimodal Imaging‐Guided Precision Surgical Therapy

“…[281][282][283] Preliminary studies demonstrated that platelets could recognize and target circulatory tumor cells (CTCs). [261,288] They explored the effects of platelets conjugated with antibodies against programmed-death ligand 1 (P-aPDL1) via systemic administration on postoperative tumor recurrence and metastasis. Furthermore, platelets can migrate to wounds for healing, which may facilitate intraoperative applications.…”

“…Furthermore, platelets can migrate to wounds for healing, which may facilitate intraoperative applications. [288] Therefore, the same group further explored genetically modified megakaryocyte-originated platelets that expressed the programmed cell death protein 1 (PD-1). [261,288] They explored the effects of platelets conjugated with antibodies against programmed-death ligand 1 (P-aPDL1) via systemic administration on postoperative tumor recurrence and metastasis.…”

“…Gu's group engineered platelets with immune checkpoint blockade for postoperative cancer immunotherapy by two methods, namely, covalent conjugation with antibodies and genetic modification. [288] Moreover, the PD-1-expressing platelets could be used as drug carriers to further improve anticancer immunity. [261] P-aPDL1 significantly prevented tumor growth and recurrence in the surgical bed of incomplete-tumor-resection models (B16F10 mouse and 4T1 carcinoma), and tumor recurrence and lung metastasis in a metastasis model with significantly increased survival time.…”

Nanomedicine‐Based Immunotherapy for the Treatment of Cancer Metastasis

“…[92][93][94] In addition to their role in shielding shear force, the formed platelet-derived shell can protect CTCs from recognition and lysis by NK cells via two main mechanisms. [95,96] Second, TGF-β will be released by activated platelets to attract neutrophils, which can inhibit the activity of NK cells.…”

“…After intravenous injection, TRAIL-DOX-PM-NV significantly prevented the pulmonary colonization of MDA-MB-231 cells injected (i.v) 30 min later ( Figure 6B). [95,96] Since native platelets would compete with the injected artificial platelets, a high dosage was thus necessary. [145] P-aPDL1-derived microparticles can target B16F10 melanoma cells intravenously injected after primary tumor removal, and inhibited their colonization in major organs after surgical removal of the primary tumor was also achieved ( Figure 6D).…”