A Unique Protein Adjuvant for Precision Immunotherapy to Prevent Recurrence of Surgically Resected Colorectal Cancer

TL;DR

A new protein adjuvant activates immune cells to prevent colorectal cancer recurrence after surgery.

Contribution

A novel protein adjuvant (GRA6Nt) is shown to effectively activate CD8+ T cells against cancer cells in a mouse model.

Findings

GRA6Nt activates CD8+ T cell cytotoxicity and IFN-γ production against CRC cells.

Immunization with GRA6Nt inhibits recurrence-like cancer growth in mice.

GRA6Nt is a protein-based adjuvant, differing from current nucleotide-based ones.

Abstract

Colorectal cancer (CRC) is the second leading cause of death among cancers. Even after curative surgical resection of CRC, 30–35% of patients have a recurrence of the cancer. The cytotoxic activity and IFN-γ production of CD8+ T cells are critical for preventing the growth of CRC. Therefore, after the surgical resection of CRC, immunizing the patients with their own resected cancer cells to effectively activate the protective CD8+ T cells specifically against their own cancer cells is a valuable approach to prevent the recurrence of cancer. In this approach, the use of a potent adjuvant that efficiently facilitates the activation of protective CD8+ T cells in immunization is critical. In contrast to the two nucleotide- or deoxynucleotide-based adjuvants currently being used in cancer immunotherapy in clinical settings, we recently identified a novel protein molecule that functions as a powerful adjuvant to activate the cytotoxic activity and IFN-γ production of CD8+ T cells specifically against CRC cells used in immunizations. In addition, immunization using this novel protein adjuvant potently inhibits the growth of identical cancer cells after its challenge implantation, which mimics the recurrence of cancer. This review will first overview the importance of activating the cytotoxic activity and IFN-γ production of CD8+ T cells in the protective immunity against CRC and highlight the uniqueness and effectiveness of the novel protein adjuvant to efficiently activate the protective CD8+ T cell immunity against target CRC cells and prevent their growth in a murine model with MC38 CRC.

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.

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