Developing an Erythrocyte-MHC-I Conjugate for Cancer Treatment

Biochemistry Bioengineering Life Sciences Immunology Oncology Medicine Cell Biology
erythrocyte MHC-I cancer treatment immune system antitumor

Developing a Novel Erythrocyte-MHC-I Conjugate for Cancer Treatment: A Revolutionary Immunotherapy

Research Background: Traditional Roles and Newly Discovered Potential

Erythrocytes, or red blood cells, are the most abundant cells in the human body, comprising approximately 70% of total cell count in adults. Traditionally recognized for their role in oxygen transport, recent studies reveal a significant role in immune system regulation. These cells, lacking nuclei, offer biocompatibility, a high surface-area-to-volume ratio, and membrane flexibility, making them ideal drug delivery vehicles. Previous research has demonstrated erythrocytes’ ability to interact with immune-related molecules such as chemokines, nucleic acids, and pathogens, e.g., regulating inflammation through the Duffy antigen receptor (DARC). Under certain pathological conditions, erythrocytes can express major histocompatibility complex (MHC) molecules, hinting at potential roles in immune modulation.

MHC class I (MHC-I) molecules are critical in cancer immunotherapy. Earlier studies explored genetically engineered erythrocytes for cancer treatment, but efficacy was limited. For example, red blood cells carrying MHC-I complexes required co-stimulatory molecules like 4-1BBL (4-1BB ligand) and interleukin-12 (IL-12) for anti-tumor effects. These approaches faced challenges such as low drug payloads and erythrocyte damage during modification, limiting therapeutic outcomes.

Against this backdrop, this study developed a novel erythrocyte conjugate containing antigen peptide-MHC-I complexes (termed MHC-I-Ery) to activate antigen-specific CD8+ T cells and explore its potential in cancer immunotherapy.

Source and Authors

This study was conducted by teams from Westlake University, Zhejiang University, and Peking University, among others, and published in the 2024 issue of Cell Discovery. Primary authors include Yuehua Liu, Xiaoqian Nie, and Xingyun Yao, with corresponding authors Xiangmin Tong, Hsiang-Ying Lee, and Xiaofei Gao.

Study Design and Methods

1. Innovation and Technological Development

The study employed an enzyme-mediated conjugation method (using a Sortase A variant, MG SrtA) to load human papillomavirus (HPV) type 16 tumor antigens (E6/E7 peptides) onto erythrocyte membranes. Key steps included:

  • Fusion Protein Design: Antigen peptides (HPV16 E6 or E7) were fused with MHC-I molecules and the Fc region of human IgG1 via genetic engineering.
  • Conjugation: The fusion protein was attached to erythrocyte membranes through a thiol-maleimide reaction, creating MHC-I-Ery conjugates.
  • Validation: Flow cytometry confirmed high conjugation efficiency (99.5%), with preserved erythrocyte integrity, morphology, and deformability. Anti-phagocytic markers (e.g., CD47) remained unaffected.

2. In Vitro Functional Validation

  • T Cell Activation: MHC-I-Ery significantly activated antigen-specific CD8+ T cells from peripheral blood mononuclear cells (PBMCs) of HPV16+ cervical cancer patients, with a 12.8-fold increase in interferon-gamma (IFN-γ) secretion.
  • Tumor Cytotoxicity: Activated CD8+ T cells displayed enhanced cytotoxicity against HPV16+ tumor cells in co-culture experiments.

3. In Vivo Mouse Studies

  • Tumor Suppression: In MC38-HPV16 tumor-bearing mice, MHC-I-Ery treatment reduced tumor volume by 71.6%.
  • Immune Modulation: Treatment increased CD8+ T cells in the spleen and reduced suppressive myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME).
  • Combination Therapy: Combining MHC-I-Ery with anti-PD-1 antibody therapy further enhanced anti-tumor effects, achieving complete tumor remission in 40% of mice.

4. Safety Assessments

  • Non-Human Primates: MHC-I-Ery exhibited excellent tolerability in rhesus monkeys. After three transfusions, erythrocyte survival rates remained stable, and no abnormalities were observed in liver function, inflammatory markers, or histopathology of major organs.

Key Findings and Significance

Major Findings:

  1. Innovation: This study is the first to demonstrate that erythrocytes conjugated solely with antigen peptide-MHC-I complexes can effectively activate the immune system and exhibit anti-tumor effects.
  2. Anti-Tumor Mechanism: MHC-I-Ery activates CD8+ T cells in the spleen, reduces suppressive immune cells in the TME, and enhances tumor-specific immunity.
  3. Safety Profile: Preclinical studies validated the safety and pharmacokinetic stability of MHC-I-Ery, paving the way for clinical development.

Clinical Potential:

  • Cancer Immunotherapy: The study offers a novel approach to cancer treatment, potentially applicable to a range of tumor antigens.
  • Autoimmune Diseases: Given erythrocytes’ immune-regulatory roles, the MHC-I-Ery platform may also be adapted for treating autoimmune diseases, such as systemic lupus erythematosus.

Conclusion and Outlook

This study presents an innovative erythrocyte-based immunotherapy platform. The long circulatory lifespan, high drug payload, and spleen-targeting properties of MHC-I-Ery make it a promising tool for cancer treatment. Future advancements in protein engineering could further enhance the efficacy of peptide-MHC-I complexes, broadening therapeutic applications.

The findings provide a significant leap in cancer immunotherapy and highlight the untapped potential of erythrocytes as immune-modulating carriers.