Abstract
Drug development targeting the most frequently mutation G12D of KRAS has great significance. As an attractive immunotherapy, cancer vaccines can overcome binding difficulties of small molecules; however, the weak immunogenicity and production difficulties of reported KRAS mutation vaccines limit their clinical application. To improve antigen-specific immune responses and Anti-Tumor effects on tumors expressing KRAS G12D mutation, we designed recombinant proteins containing KRAS peptide (amino acids 5–21) with G12D (called SP) in two forms: DTT-SP4 and DTSP. DTT-SP4 was constructed by fusing four copies of SP to the C-terminal of the translocation domain of diphtheria toxin (DTT), and DTSP was constructed by grafting SP onto DTT. The two vaccines in combination with aluminum hydroxide (Alum) and cytosine phosphoguanine (CpG) successfully induced conspicuous SP-specific humoral and cellular immune responses, and displayed prominent protective and therapeutic Anti-Tumor effects in mouse CT26 tumor models. Surprisingly, the DTSP-treated group displayed better Anti-Tumor effects in vivo compared with the DTT-SP4-treated and control groups. Moreover, 87.5 and 50% of DTSP-treated mice in the preventive and therapeutic models were tumor free, respectively. Notably, in the DTSP-treated group, the interferon-γ (IFN-γ) expression of T cells in vitro and the T-helper 1 (Th1)–related cytokine expression in tumor tissues indicated that the activated Th1 immune response may be involved in Anti-Tumor activity. Furthermore, DTSP treatment remarkably altered the subpopulation of T cells in splenocytes and tumor-infiltrating lymphocytes. The percentage of effector CD8+ T cells increased, whereas that of immunosuppressive CD4+Foxp3+ T cells remained reduced in the DTSP group. Dramatic tumor-inhibitory effects of DTSP, which is easily prepared, make it a more attractive strategy against KRAS G12D tumors.
Highlights
KRAS mutations, as common driver mutations, are mainly observed in pancreatic cancer (PDA), colorectal cancer (CRC), and lung cancer, with mutation frequencies of 97.7, 44.7, and 30.9%, respectively [1]
Mice administered with diphtheria toxin (DTT)-FDmut showed better Anti-Tumor efficacy than those administered with DTT-FDwt in the KRAS G12D mutation containing CT26 tumor model (Figures 1C,D)
An in vivo Anti-Tumor effect can theoretically be achieved by directly targeting KRAS mutations through immunotherapies, as long as KRAS mutations are displayed on tumor cells [25]
Summary
KRAS mutations, as common driver mutations, are mainly observed in pancreatic cancer (PDA), colorectal cancer (CRC), and lung cancer, with mutation frequencies of 97.7, 44.7, and 30.9%, respectively [1]. Mutant KRAS promotes the proliferation of cancer cells and the infiltration of immunosuppressive cells such as regulatory T cells (Tregs) and reduces the KRAS Vaccine Elicit Anti-Tumor Effects proportion of CD8+ T cells in tumors [2,3,4,5,6]. Genetic aberrations such as KRAS mutations are specific to cancer and do not exist in normal tissues [7]. For other KRAS mutations, small molecule drugs still remain elusive, with no effective targeted therapy at present for patients with KRAS-mutant cancer [1, 9, 11]
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