The identification of effective tumor-suppressing neoantigens using a tumor-reactive TIL TCR-pMHC ternary complex

• Published in: Experimental & molecular medicine 2024-06, Vol.56 (6), p.1461-1471
• Main Authors: Kim, Sang Hoon, Lee, Bo Ryeong, Kim, Sung-Min, Kim, Sungsik, Kim, Min-seok, Kim, Jaehyun, Lee, Inkyu, Kim, Hee-Soo, Nam, Gi-Hoon, Kim, In-San, Song, Kyuyoung, Choi, Yoonjoo, Lee, Dong-Sup, Park, Woong-Yang
• Format: Article
• Language: English
• Subjects: 13/31; 38/39; 45/22; 45/23; 45/90; 45/91; 631/114/1305; 631/250/590/2030; 631/67/1059/2325; 64/60; Antitumor activity; Artificial intelligence; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer immunotherapy; Cancer therapies; Cancer vaccines; CD8 antigen; Deep learning; Hepatocellular carcinoma; Immunogenicity; Liver cancer; Lymphocytes; Lymphocytes T; Medical Biochemistry; Melanoma; Molecular Medicine; Neoantigens; Next-generation sequencing; Peptides; Predictions; Stem Cells; T cell receptors; Tumor suppression; Tumor-infiltrating lymphocytes; Vaccines
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-024-01259-2

Neoantigens are ideal targets for cancer immunotherapy because they are expressed de novo in tumor tissue but not in healthy tissue and are therefore recognized as foreign by the immune system. Advances in next-generation sequencing and bioinformatics technologies have enabled the quick identification and prediction of tumor-specific neoantigens; however, only a small fraction of predicted neoantigens are immunogenic. To improve the predictability of immunogenic neoantigens, we developed the in silico neoantigen prediction workflows VACINUS pMHC and VACINUS TCR: VACINUS pMHC incorporates physical binding between peptides and MHCs (pMHCs), and VACINUS TCR integrates T cell reactivity to the pMHC complex through deep learning-based pairing with T cell receptors (TCRs) of putative tumor-reactive CD8 tumor-infiltrating lymphocytes (TILs). We then validated our neoantigen prediction workflows both in vitro and in vivo in patients with hepatocellular carcinoma (HCC) and in a B16F10 mouse melanoma model. The predictive abilities of VACINUS pMHC and VACINUS TCR were confirmed in a validation cohort of 8 patients with HCC. Of a total of 118 neoantigen candidates predicted by VACINUS pMHC , 48 peptides were ultimately selected using VACINUS TCR . In vitro validation revealed that among the 48 predicted neoantigen candidates, 13 peptides were immunogenic. Assessment of the antitumor efficacy of the candidate neoepitopes using a VACINUS TCR in vivo mouse model suggested that vaccination with the predicted neoepitopes induced neoantigen-specific T cell responses and enabled the trafficking of neoantigen-specific CD8 + T cell clones into the tumor tissue, leading to tumor suppression. This study showed that the prediction of immunogenic neoantigens can be improved by integrating a tumor-reactive TIL TCR-pMHC ternary complex. TCR-Paired Neoantigen Prediction Enhances T Cell Response for Cancer Therapy Cancer scientists have created a new way to identify and choose neoantigens (new proteins on cancer cells) for use in cancer vaccines. The research, led by Woong-Yang Park, included 33 patients with different cancer types. The scientists used a mix of computer-based prediction techniques and lab-based tests to find the most effective neoantigens. The results showed that the new technique, named VACINUS, was better at predicting effective neoantigens than older methods. The scientists concluded that the VACINUS technique could improve the immune response of predicted neoanti