X. Shirley Liu, Ruoxu Dou, Binbin Wang, Catherine J. Wu, Sachet A. Shukla, Jun Liu, Taiwen Liu, Jinzeng Wang, Nir Hacohen, Bo Li, and Stephen Hodi
T cells play a critical role in antitumor immunity and are the primary targets in many immunotherapies. However, the study of tumor-infiltrating T cells has been complicated by the extremely diverse repertoire of T cell receptors, characterized by the complementarity determining region 3 (CDR3). Here using our newly developed algorithm, we studied the CDR3 sequences of tumor infiltrating T cells in 9,142 RNA-seq samples across 29 diseases. In total, we assembled over 600 thousands CDR3 sequences, covering the α, β, γ, δ chains. TRBV genes usage, CDR3 sequence length and conservation of infiltrating T cells resembled those in the peripheral blood of healthy donors in many tumors, except brain and kidney cancers. About 20% of the CDR3 calls were shared in multiple individuals. T cell clonotypes carrying these CDR3 sequences are known as the ‘public T cells’. In this work, we found that public T cell CDR3 amino acid (AA) sequences are shorter compared to the private ones and the middle 3 positions of the private CDR3 sequences were enriched for hydrophobic AAs. This finding potentially suggests that private T cell clonotypes in the tumors have greater potential to recognize neoantigens. We defined clonotype per kilo-reads (CPK) to measure the diversity of T cell repertoire and identified a strong positive association between CPK and tumor mutation load, implying that neoantigens may diversify the infiltrating T cell population. In addition, we predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers based on their strong associations with CPK. Finally, we identified 3 potential immunogenic somatic mutations based on their co-occurrence with CDR3 sequences. One of them, PRAMEF4 F300V, was predicted to bind strongly to both MHC-I and MHC-II, with matched HLA types in its carriers. Our analyses have the potential to simultaneously identify immunogenic neoantigen and the tumor-reactive T-cell clonotype. Citation Format: Bo Li, Taiwen Liu, Binbin Wang, Jinzeng Wang, Sachet Shukla, Ruoxu Dou, Stephen Hodi, Catherine Wu, Nir Hacohen, Jun Liu, X. Shirley Liu. Landscape of tumor-infiltrating T-cell repertoire of human cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-264.