To improve the accuracy of HLA-II ligand prediction, particularly for identification of neoantigens in tumors, Abelin, Harjanto, and Malloy et al. developed MAPTAC – a mono-allelic profiling method that quickly profiled >40 HLA-II alleles – and used the MAPTAC data to train the novel binding prediction algorithm neonmhc2. Binding motifs for many HLA-II alleles were sensitive to the peptide-loading chaperone HLA-DM. Neonmhc2 predicted immunogenic HLA-II neoantigens not predicted by NetMHCIIpan; gene expression, protein localization, and processing enhanced predictions. APCs, rather than tumor cells, drove HLA-II presentation within the TME.
Increasing evidence indicates CD4(+) T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.
Author Info: (1) Neon Therapeutics, Cambridge, MA 02139, USA. (2) Neon Therapeutics, Cambridge, MA 02139, USA. (3) Neon Therapeutics, Cambridge, MA 02139, USA. (4) Neon Therapeutics, Cambridge,
Author Info: (1) Neon Therapeutics, Cambridge, MA 02139, USA. (2) Neon Therapeutics, Cambridge, MA 02139, USA. (3) Neon Therapeutics, Cambridge, MA 02139, USA. (4) Neon Therapeutics, Cambridge, MA 02139, USA. (5) Neon Therapeutics, Cambridge, MA 02139, USA. (6) Neon Therapeutics, Cambridge, MA 02139, USA. (7) Neon Therapeutics, Cambridge, MA 02139, USA. (8) Neon Therapeutics, Cambridge, MA 02139, USA. (9) Neon Therapeutics, Cambridge, MA 02139, USA. (10) Neon Therapeutics, Cambridge, MA 02139, USA. (11) Neon Therapeutics, Cambridge, MA 02139, USA. (12) Neon Therapeutics, Cambridge, MA 02139, USA. (13) Neon Therapeutics, Cambridge, MA 02139, USA. (14) Neon Therapeutics, Cambridge, MA 02139, USA. (15) Neon Therapeutics, Cambridge, MA 02139, USA. (16) Neon Therapeutics, Cambridge, MA 02139, USA. (17) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (18) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (19) Neon Therapeutics, Cambridge, MA 02139, USA. (20) Neon Therapeutics, Cambridge, MA 02139, USA. (21) Neon Therapeutics, Cambridge, MA 02139, USA. (22) Neon Therapeutics, Cambridge, MA 02139, USA. (23) Neon Therapeutics, Cambridge, MA 02139, USA. (24) Neon Therapeutics, Cambridge, MA 02139, USA. (25) Neon Therapeutics, Cambridge, MA 02139, USA. (26) Neon Therapeutics, Cambridge, MA 02139, USA. Electronic address: mrooney@neontherapeutics.com.
