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A Unique Protein Adjuvant for Precision Immunotherapy to Prevent Recurrence of Surgically Resected Colorectal Cancer
Yasuhiro Suzuki1,2, Rajesh Mani1, B Mark Evers2,3
1Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Abstract:
Effectively activating protective CD8+ T cell immunity specifically against cancer antigens is an important pathway to prevent the growth of various types of cancers. A major obstacle in this approach is variations in cancer antigens among patients. A valuable material to overcome the antigen variation among cancer patients is the use of each individual's own cancer cells for immunization. In colorectal cancer (CRC), approximately one-third of the patients who receive curative surgical resection have a recurrence of cancer. Therefore, the use of surgically resected CRC for immunotherapy to specifically activate the protective CD8+ T cells against their own cancer cells is a valuable approach to prevent the recurrence of cancer. However, since cancer-specific antigens are often not strongly immunogenic, a potent immunostimulant is required as an adjuvant for efficiently facilitating the activation of cancer-specific protective CD8+ T cells. We recently identified that a protein molecule, the amino-terminus region of the dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, selectively activates innate expressions of IFN-γ and IL-18 and functions as a powerful adjuvant when used in immunization with nonreplicable (treated with mitomycin C or irradiated) MC38 CRC cells to potently activate the cytotoxic activity and IFN-γ production of CD8+ T cells against cancer cells. In addition, immunization using the GRA6Nt protein adjuvant effectively inhibits the growth of identical CRC cells after its challenge implantation, which mimics a recurrence of the surgically resected CRC used for the immunizations. In contrast to the two nucleotide- or deoxynucleotide-based Toll-like receptor agonists currently being used as adjuvants in cancer immunotherapy in clinical settings, GRA6Nt is a protein molecule. Thus, the rGRA6Nt protein adjuvant provides a new pathway in cancer immunotherapy to effectively activate the protective CD8+ T cells specific for the individual's cancer cells to prevent the recurrence of surgically resected CRC in patients.
Insights
A novel protein adjuvant, GRA6Nt from Toxoplasma gondii, effectively activates CD8+ T cell immunity against individual cancer cells. This approach shows promise for preventing colorectal cancer recurrence after surgery.
Area of Science:
- Immunology
- Oncology
- Parasitology
Background:
- Activating CD8+ T cell immunity against cancer antigens is crucial for cancer prevention.
- Cancer antigen variability among patients necessitates personalized immunotherapy approaches.
- Colorectal cancer (CRC) recurrence after surgery highlights the need for effective preventative strategies.
Purpose of the Study:
- To evaluate the GRA6Nt protein from Toxoplasma gondii as a potent adjuvant for cancer immunotherapy.
- To assess the ability of GRA6Nt to activate protective CD8+ T cell responses against colorectal cancer.
- To determine if GRA6Nt-based immunization can prevent tumor recurrence in a preclinical model.
Main Methods:
- Immunization of mice with nonreplicable MC38 colorectal cancer cells and the GRA6Nt protein adjuvant.
- Assessment of CD8+ T cell cytotoxic activity and IFN-γ production.
- Evaluation of tumor growth inhibition and prevention of tumor recurrence after challenge implantation.
Main Results:
- GRA6Nt selectively activated innate IFN-γ and IL-18 expressions.
- Immunization with GRA6Nt and cancer cells potently activated CD8+ T cell cytotoxic activity and IFN-γ production.
- GRA6Nt-based immunization significantly inhibited tumor growth and prevented recurrence of colorectal cancer.
Conclusions:
- The GRA6Nt protein functions as a powerful adjuvant, enhancing CD8+ T cell responses against cancer-specific antigens.
- GRA6Nt offers a novel protein-based adjuvant strategy for cancer immunotherapy, distinct from nucleotide-based TLR agonists.
- This approach holds potential for preventing the recurrence of surgically resected colorectal cancer by activating patient-specific anti-cancer immunity.
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