Cancer vaccines are a type of immune therapy that seeks to modulate the host’s immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes.

Background Lynch syndrome (LS), caused by germline pathogenic variants in the mismatch repair genes, leads to high rates of frameshift-derived neopeptide (FSDN) expression due to microsatellite instability (MSI). While colorectal cancer (CRC) prevention is effective, most LS-related tumors lack such strategies. Cancer vaccines targeting FSDNs offer a promising approach for immune interception in LS. This study aimed to identify and validate LS-related FSDNs to develop vaccines for cancer prevention. Methods We identified LS-related coding MS mutations and predicted FSDN with high coverage on common Human Leukocyte Antigen (HLA)-I and II alleles. We validated FSDN-associated mutations in colorectal adenomas (CrAD), endometrial cancers (EC), and CRC samples from patients with LS, non-LS tumors, and cell lines. Immunogenicity was assessed through interferon (IFN)-γ enzyme-linked immunospot and flow cytometry analysis of tissue-infiltrating lymphocytes (TILs) from LS carriers. Results We prioritized 53 HLA-I and 45 HLA-II FSDNs in MSI tumors using in silico predictions. Validation revealed 86.7% of FSDN-associated mutations present in LS-CRC samples, with a median of 7.67 (6.5–9) mutations in CrADs and 6.02 (2–10) in CRCs. Sequencing of CrAD and EC samples showed 95% and 77.5% of predicted FSDN-associated mutations, respectively. MSI cancer cell lines transcribed 69.8% of FSDNs. Immunogenicity assays showed that 71% of potential FSDNs elicited IFN-γ responses, with a median of 7.37 (1–10.75) HLA-I and 6 (2–5.75) HLA-II FSDNs per patient. After prioritizing 24 FSDN, in a cohort of 19 LS-derived samples (4 CrAD and 15 normal mucosa), 52% (10/19) demonstrated T-cell reactivity to an HLA-I neoantigen pool. CD8+CD137+ activation markers increased significantly (p=0.037) over time and peptide-specific cells were detected by pentamer staining. Conclusions Our predicted FSDN set has optimal coverage among LS carriers and can induce IFN-γ inflammatory responses in LS-derived TILs, offering an opportunity for vaccine development.

Encapsulation of water-soluble bioactive compounds for enabling specific accumulation in tumor locations, while avoiding premature clearance and/or degradation in the bloodstream, is one of the main hallmarks in nanomedicine, especially that of NIR fluorescent probes for cancer theragnosis. The herein reported technology furnishes water-dispersible double-walled polyurethane-polyurea hybrid nanocapsules (NCs) loaded with indocyanine green (ICG-NCs), using a versatile and highly efficient one-pot and industrially scalable synthetic process based on the use of two different prepolymers to set up the NCs walls. Flow cytometry and confocal microscopy confirmed that both ICG-loaded NCs internalized in monocyte-derived dendritic cells (moDCs). The in vivo analysis of xenograft A375 mouse melanoma model revealed that amphoteric functionalization of NCs’ surface promotes the selective accumulation of ICG-NCs in tumor tissues, making them promising agents for a less-invasive theragnosis of cancer.