Self-antigen MASH2 combined with the AS15 immunostimulant induces tumor protection in colorectal cancer mouse models.

Abstract

Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for colorectal cancer immunotherapy. We assessed immunogenicity and antitumor potential of recombinant MASH2 protein combined with AS15 immunostimulant (recMASH2+AS15) in CB6F1 and Apc+/Min-FCCC mice. CB6F1 mice received 4 injections of recMASH2+AS15 or AS15 alone before challenge with TC1-MASH2 tumor cells (Tumor Challenge). Apc+/Min-FCCC mice received 9 injections of recMASH2+AS15 or vehicle (phosphate buffer saline [PBS] or AS15 alone), before (two independent Prophylactic Studies) or after (Immunotherapy) colon adenomas were detectable by colonoscopy. CB6F1 mice immunized with recMASH2+AS15 had a significantly smaller mean tumor size and improved survival rate compared to controls (104 mm2 vs. 197 mm2 [p = 0.009] and 67% vs. 7% [p = 0.001], respectively). In Prophylactic Study 1, the mean number of colon adenomas was significantly lower in Apc+/Min-FCCC mice receiving recMASH2+AS15 compared to PBS (1.8 [95% confidence interval 1.0-3.3] vs. 5.2 [3.7-7.4], p = 0.003). Fewer microadenomas were observed in recMASH2+AS15 groups compared to PBS in both Prophylactic Studies (Study 1: mean 0.4 [0.2-1.0] vs. 1.5 [0.9-2.4], p = 0.009; Study 2: 0.4 [0.2-0.6] vs. 1.1 [0.8-1.5], p = 0.001). In the Immunotherapy Study, fewer colon adenomas tended to be observed in recMASH2+AS15-treated mice (4.1 [2.9-6.0]) compared to controls (AS15 4.7 [3.3-6.6]; PBS 4.9 [3.5-6.9]; no significant difference). recMASH2+AS15 induced MASH2-specific antibody and CD4+ responses in both mouse models. recMASH2+AS15 partially protected mice against MASH2-expressing tumors and reduced spontaneous colorectal adenomas in Apc+/Min-FCCC mice, indicating that MASH2/HASH2 antigens are targets for colorectal cancer immunotherapy.

• Authors: Clément R Rioux, Margie L Clapper, Harry S Cooper, Jean Michaud, Natalie St Amant, Hossein Koohsari, Laura Workman, Esther Kaunga, Harvey Hensley, Anthony Pilorget, Catherine Gerard
• Journal: PloS one (PLoS One) Vol. 14 Issue 1 Pg. e0210261 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 30682058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Ascl2 protein, mouse
• Autoantigens
• Basic Helix-Loop-Helix Transcription Factors
• Cancer Vaccines
• Recombinant Proteins

Topics

• Adjuvants, Immunologic (administration & dosage)
• Animals
• Apoptosis
• Autoantigens (immunology)
• Basic Helix-Loop-Helix Transcription Factors (genetics, immunology)
• Cancer Vaccines (administration & dosage, immunology)
• Cell Proliferation
• Colorectal Neoplasms (immunology, metabolism, prevention & control)
• Disease Models, Animal
• Drug Therapy, Combination
• Female
• Genes, APC
• Humans
• Immunotherapy
• Male
• Mice
• Recombinant Proteins (genetics, immunology)
• Tumor Cells, Cultured