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

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.
Competing Interests: CR, JM, NSA and HK were employees of the GSK group of companies during the conduct of the study. AP and CG are employed by the GSK group of companies. AP, CG, JM and HK hold shares in the GSK group of companies as part of their employee remuneration. This does not alter our adherence to PLOS ONE policies on sharing data and materials. MC, EK, LW, HH and HC have no conflict of interest to disclose.