Identification of Public Neoantigens with Broad HLA Class I Coverage as Candidates for Off-the-Shelf Cancer Vaccine Development in Colorectal Cancer

Diem TP Tran¹Bui Que Tran Nguyen¹Huu Thinh Nguyen²Thi Mong Quynh Pham¹Dinh Viet Linh Nguyen¹Thanh Nhan Nguyen¹Thi Kim Cuong Ho¹Thi Tuong Vy Nguyen¹Pham Trung Dung Nguyen¹Duc Huy Tran²Thanh Sang Tran²Truong-Vinh Ngoc Pham²Minh-Triet Le²Hoa Giang¹Hoai Nghia Nguyen¹Minh Duy Phan¹Le Son Tran^1*

• ¹Medical Genetics Institute (Vietnam), Ho Chi Minh, Vietnam
• ²University Medical Center Ho Chi Minh City, Ho Chi Minh City, Vietnam

Shared neoantigens derived from recurrent mutations offer strong potential for off-the-shelf (OTS) cancer immunotherapies but are often limited by population-specific HLA diversity and suboptimal immunogenicity. To address this, we developed a colorectal cancer (CRC)-specific OTS neoantigen panel by integrating TCGA mutation data with HLA class I binding predictions across 68 alleles (18 HLA-A, 34 HLA-B, 16 HLA-C), achieving >90% population coverage in both Asian and Caucasian groups. The panel comprises 73 recurrent nonsynonymous mutations, each yielding at least one predicted HLA-I–restricted neoepitope. In a Vietnamese CRC cohort (n = 67), 58% of patients had at least one matched neoantigen, with mutation frequency strongly correlating with HLA presentation—particularly through HLA-A alleles. Functional validation in seven patients confirmed robust CD8⁺ T cell responses against TP53_R273H, supported by IFN-γ ELISpot and single-cell RNA-seq profiling. Reactive T cells displayed activation signatures consistent with both cytotoxic and stem-like memory phenotypes. These findings identify TP53_R273H as a clinically relevant shared neoantigen and demonstrate the translational potential of our population-tailored OTS neoantigen panel for CRC.