Identification of patient-specific and tumor-shared T cell receptor sequences in renal cell carcinoma patients

Abstract

A major requirement for cancer immunotherapy is the development of biomarkers for prognosis and for monitoring therapy response. In an attempt to evaluate the immune response of renal cell carcinoma (RCC) patients, tumor lesions and / or blood samples from 12 RCC patients underwent deep T cell receptor (TCR) sequencing. Despite the low number of samples, different TCR distribution patterns could be detected. Most of the RCC patients presented "patient-specific" TCR sequences, and those clonotypes were present at higher frequency in tumor lesions suggesting a specific extravasation from the blood. Comparison among the tumor samples revealed also "patient-shared" TCR patterns. Indeed, a central core of 16 different TCRs were shared by 3 patients, whereas other 6 patients shared between 4 and 6 TCR sequences, with two sub-groups sharing 12 to 17 different clonotypes. The relative frequencies of shared clonotypes were very different varying from < 1% to a maximum of 37% of the total TCR repertoire. These data confirm the presence of tumor-specific TCR within the cancer tissue and suggest the existence of shared epitopes among different patients that might be used as targets for tumor immunotherapy.

Biophysicochemical Motifs in T-cell Receptor Sequences Distinguish Repertoires from Tumor-Infiltrating Lymphocyte and Adjacent Healthy Tissue

“…Therefore, we reasoned that patients with the same cancer type or subtype may have cytotoxic T-cell responses against a common set of antigens. Indeed, there is evidence for shared immunoreactivity, as well as for shared TCR sequences (4)(5)(6)(7)(8)(9)(10). We further reasoned that if these T-cell responses could be detected, particularly early in the disease course, they could serve as an important addition to the suite of methods under development for the early detection of cancer.…”

“…The technology has enabled novel approaches for diagnosing and prognosticating diseases with a driving immune component by identifying repertoire patterns associated with clinical phenotypes. Most studies have been purely descriptive and looked for shared amino acid sequences among patients with a common phenotype (7,8), looked for clusters of sequences overrepresented in one phenotype relative to another (13), or compared repertoire-level summary statistics, such as diversity, between phenotypes (reviewed in refs. 12,14,15).…”

Patient‐shared TCRβ‐CDR3 clonotypes correlate with favorable prognosis in chronic hepatitis B

“…To facilitate the test of the hypothesis that CHB-enriched T cells are abundant and unique to the disease, we generated HBV peptide specific T-cell lines and measured the response against HBV using four different peptide-pentamer complexes: HLA-A0201-FLLSLGIHL (HBp573, derived from the HBV polymerase protein 573-581), HLA-A0201-FLLTRILTI (HBe183, derived from the HBV envelope protein 183-191), HLA-A0201-FLPSDFFPSV (HBc18, derived from the HBV core antigen protein [18][19][20][21][22][23][24][25][26][27], and HLA-A1101-YVNVNMGLK (HBc88, derived from the HBV core antigen protein 88-96). A combination of FACS and TCRß cloning was used to quantitatively characterize epitope-specific antiviral responses ( Fig.…”

“…The configuration of the peripheral lymphocyte repertoire is critical for determining the robustness of an immune response against particular antigens . Each repertoire has millions of TCR sequences with enormous diversity, however, shared clonotypes were found in patients with the same disease in several tumor or chronic viral infectious diesases . Specifically, TCR usage or featured TCR clonotypes exemplify a signature of past and ongoing immune responses .…”

Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma

“…However, a major challenge in the field is the technical difficulty in identifying the cognate antigens associated with clonally expanded TCRs. 38 …”