Novel Protein Adjuvant Activating Innate IFN-γ and IL-18 Expression and Inducing Rejection of Implanted Colorectal Cancer Following Immunotherapy Using This Adjuvant in Mice
Main Article Content
Abstract
Our recent study demonstrated that immunizations with nonreplicable MC38 colorectal cancer cells plus a novel recombinant protein adjuvant, the amino-terminus region of dense granule protein 6 (rGRA6Nt) of Toxoplasma gondii (a protozoan parasite), effectively activate the cancer cell-specific CD8+ T cytotoxic cells and inhibit the growth of implanted tumors of the identical cancer cells after its challenge implantation. In the present study, we first examined whether rGRA6Nt activates mRNA expression for IFN-g, IL-12, IL-15, and IL-18, which are known to assist an activation of the CD8+ T cells, in innate immune cells. Following an intraperitoneal injection of rGRA6Nt (40 mg) into SCID mice deficient in both T and B cells, markedly increased levels of mRNA for only IFN-g and IL-18 were detected in their peritoneal exudate innate immune cells. When C57BL/6 mice were immunized with nonreplicable MC38 colorectal cancer cells plus rGRA6Nt adjuvant twice and challenged with replication-capable cancer cells of the identical colorectal cancer, more than one fifth (22.2%, 6/27) of the immunized mice rejected the growth of the implanted tumors, whereas none (0/27, P<0.05) of unimmunized control mice rejected the implanted tumors. These results indicate that rGRA6Nt protein adjuvant has a unique capability to selectively activate expression of IFN-g and IL-18 in innate immune cells, and that immunizations with nonreplicable cancer cells in combination with this protein adjuvant can induce a protection to reject the growth of the identical tumor cells after its challenge implantation in a significant portion of the immunized mice.
Keywords:
adjuvant, cancer immunotherapy, IFN-g, IL-18, innate immunity, protective immunity, cancer rejection
Article Details
How to Cite
MANI, Rajesh; EVERS, B. Mark; SUZUKI, Yasuhiro.
Novel Protein Adjuvant Activating Innate IFN-γ and IL-18 Expression and Inducing Rejection of Implanted Colorectal Cancer Following Immunotherapy Using This Adjuvant in Mice.
Medical Research Archives, [S.l.], v. 13, n. 6, june 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6615>. Date accessed: 15 july 2025.
doi: https://doi.org/10.18103/mra.v13i6.6615.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. H. Dong, G. Zhu, K. Tamada, L. Chen, B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat. Med, 1999, 5:1365-9.
3. G.J. Freeman, A.J. Long, Y. Iwai, K. Bourque, T. Chernova, H. Nishimura, L.J. Fitz, N. Malenkovich, T. Okazaki, M.C. Byrne, H.F. Horton, L. Horton, L. Fouser, L. Carter, V. Ling, M.R. Bowman, B.M. Carreno, M. Collins, C.R. Wood, T. Honjo, Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med, 2000, 192:1027-34.
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22. Sa, Q., et al., Cutting Edge: IFN-gamma Produced by Brain-Resident Cells Is Crucial To Control Cerebral Infection with Toxoplasma gondii. J. Immunol. 2015, 195: 796-800.
23. J.R. Baird, K.T. Byne, P.H. Lizotte, S. Toraya-Brown, U.K. Scarlett, M.P. Alexander, M.R. Sheen, B.A. Fox, M. Bosenberg, D.W. Mullins, M.J. S. Fiering. Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge. J. immunol. 2013, 190: 469-78.
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38. A. Tiwari, R. Hnnah, J. Lutshumba, E. Ochiai, L.M. Weiss, Y. Suzuki. Penetration of CD8+ cytotoxic T cells into large target, tissue cysts of Toxoplasma gondii, leads to its elimination. Am. J. Pathol. 2019, 189: 1594-1607.
39. C. Mercier, M.F. Cesbron-Delauw. Toxoplasma secretory granules: one population or more? Trends Parasitol. 2015, 31: 60-71