Landscape of tumor-infiltrating T cell repertoire of human cancers

Abstract

We developed a computational method to infer the complementarity determining region 3 (CDR3) sequences of tumor infiltrating T-cells in 9,142 RNA-seq samples across 29 cancer types. We identified over 600 thousand CDR3 sequences, including 15% with full-length. CDR3 sequence length distribution and amino acid conservation, as well as variable gene usage of infiltrating T-cells in many tumors, except brain and kidney cancers, resembled those in the peripheral blood of healthy donors. We observed a strong association between T-cell diversity and tumor mutation load, and predicted SPAG5 and TSSK6 as putative immunogenic cancer/testis antigens in multiple cancers. 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 neoantigens and the tumor-reactive T-cell clonotypes.

Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination

“…The T‐cell repertoire of tumor‐infiltrating cells has been studied to look for signatures of immunogenicity,52, 53, 54 and the overlap between the tumor and blood repertoires was shown to predict survival in glioblastoma patients 55. In addition, the tumor‐specific TCRs have been reported to be shared in the tumor‐infiltrating and blood T‐cell repertoires of breast cancer 56…”

The “Achilles' Heel” of Cancer and Its Implications for the Development of Novel Immunotherapeutic Strategies

“…Tumors with a high mutational load and resulting neoantigen burden may give rise to a more diverse intratumoral T-cell repertoire caused by the large number of antigens presented to the immune system. In line with this, an association between T-cell diversity and mutational load has previously been reported through the analysis of reconstructed CDR3 regions from RNAseq data of samples within the TCGA database (Li et al 2016).…”

The role of the tumour microenvironment in immunotherapy

“…A number of recent publications found correlations between the mutational load uniquely present in cancer cells (neoantigens) and T cell infiltration of tumours (Brown et al 2015, Li et al 2016, Senbabaoglu et al 2016. High-throughput epitope screening of cancer mutanomes revealed that only a small fraction of mutated peptides in cancer cells produced T cell reactivity (Lu et al 2014, Yadav et al 2014, Linnemann et al 2015 Schumacher & Schreiber 2015).…”