TCR Sequencing

TCR sequencing has enabled the identification of new targets for T-cell-based therapies and the development of personalized cancer vaccines. It is a powerful tool that can provide insights into the immune system’s response to cancer. Contact us on how Provenance supports research for TCR sequencing.

TCR (T-cell receptor) sequencing plays a critical role in advancing our understanding of immunology and medicine. TCR Sequencing is a technique used to identify and analyze the genetic sequences of T-Cell Receptors (TCRs). It allows a comprehensive determination of the TCR sequences in individuals. TCRs are proteins found on the surface of T-cells, they are responsible for recognizing specific antigens and initiating an immune response. The immune response recognition can be stimulated naturally or in response to treatment like vaccines. TCR sequencing primarily helps us identify respective TCR sequences and antigens, a holy grail as neither the sequence nor the antigen can be predicted by computers if one is unknown. The technology is not yet apart of clinical practice and available to patients because of its technical challenge and the knowledge necessary on T cell biology. Additionally, TCR sequencing can contribute to the basic characterization of tumor heterogeneity, tumor evolution, and can also be used to identify neoantigen-specific TCRs from tumor specimens1,2. This can help in the development of personalized cancer vaccines and T cell-based immunotherapies. TCR sequencing serves as a cornerstone in the exploration of immune response mechanisms, disease progression, and the development of innovative strategies for disease prevention and treatment in the fields of immunology and medicine.

TCR sequencing can be combined with single-cell RNA sequencing to investigate gene expression, clonal expansion, TCR lineage, and antigen specificity of T cells at the tumor site and its adjacent tissues1. This knowledge is crucial to understand the variety in T cells and their respective function. It is the prerequisite to guide personalized treatment for patients in the future.

Use of TCR Sequencing in Cancer Research and Treatment

With the progress in technology, it has become feasible to detect T-cell receptors that specifically target common cancer antigens. This targeting of cancer-specific antigens contributes to tumor profiling, the development of personalized cancer vaccines, and the monitoring of immune responses.

Tumor profiling is one of the many ways that TCR Sequencing can aid in the cancer treatment landscape. This technique helps characterize T-cell repertoire within tumors, providing insights into the immune response against cancer and identifies potential immunotherapy targets. A research article recently published discusses the relationship between global metrics characterizing the TCR repertoire and the results of functional responses. The characteristics of TCR repertoires in cancer patients were investigated to determine their potential as prognostic and predictive biomarkers for therapy response. Additionally, the impact of TCR rearrangement following immunotherapy on clinical outcomes was evaluated3.

TCR Sequencing can aid in the development of personalized cancer vaccines. These vaccines are designed to train the immune system to recognize and attack each patient’s unique tumor cells. They have the potential to induce long-term immunological memory against cancer. The use of TCR Sequencing was observed in a case study involving a patient with metastasized pancreatic ductal carcinoma. A multi-peptide vaccine was administered, targeting the specific mutations of the pancreatic tumor. TCR analysis showed a vaccine-reactive TCR repertoire with specificity of clones and indications that vaccine-reactive T cells persisted over time. The observed T-cell responses possibly contributed to the patient’s clinical outcome, with the individual alive six years after the initial diagnosis 4.

TCR Sequencing also allows us to track and quantify immune response against targets and can be used to predict therapy response and survival outcomes for patients. This was explored in a study involving with head and neck squamous cell carcinoma (HNSCC) treated with the combination of cetuximab and nivolumab. The study demonstrated the prognostic potential for TCR repertoire clonotyping in pretreatment peripheral blood mononuclear cells. Pretreatment peripheral TCR repertoires derived from PBMC can serve as biomarkers for immunotherapy in HNSCC5.

Highlighting Academic Centers: Recent Use of TCR Sequencing

Considering the progress in TCR sequencing technology, we are spotlighting most recently published articles and advancements within academic institutions over the past two years. It is important to acknowledge the significant progress being made by numerous other institutions in this field.

A phase II trial was conducted on the use of elotuzumab, lenalidomide, and dexamethasone (EloLenDex) in patients with high-risk SMM. The study performed single-cell RNA and TCR sequencing on bone marrow and peripheral blood samples. Early EloLenDex treatment was safe, effective, and provided a complete analysis of how immune cell composition and TCR repertoire diversity changed in patients6.

A recent study explored newly developed technologies to obtain neoantigen-specific T cells from blood and tumors from patients with metastatic melanoma with or without response to anti-programmed death receptor 1 (PD-1) immunotherapy. The study revealed that a T cells with unique neoTCR sequences (T cell clonotypes) effectively recognized a limited number of mutations from seven patients who maintained favorable clinical outcomes over an extended period7.

An author manuscript delves into the tracking of T-cell clonotypes across tissues, shedding light on the clonal origins and enduring persistence of tumor-specific T cells during immune checkpoint blockade (ICB). The study used single-cell RNA and TCR sequencing to analyze and track T cells in patients with lung cancer after ICB. Longitudinal tracking of tumor-specific CD8+ and CD4+ T cells reveals that they can remain in the peripheral blood for years after ICB therapy8.

Future of TCR Sequencing

TCR sequencing has become an important tool for developing cancer immunotherapies. It has enabled the identification of new targets for T-cell-based therapies and the development of personalized cancer vaccines2. It is a powerful tool that can provide insights into the immune system’s response to cancer. Potential advancements of this technology can combine TCR Sequencing with other technologies, improved the sensitivity and specificity, and allow for single-cell TCR Sequencing. It can transform our understanding of the immune system leading us to the development of new and more effective treatments.


  1. Direct identification of neoantigen-specific TCRs from tumor specimens by high-throughput single-cell sequencing | Journal for ImmunoTherapy of Cancer.
  2. Frank, M. L. et al. T-Cell Receptor Repertoire Sequencing in the Era of Cancer Immunotherapy. Clin. Cancer Res. 29, 994–1008 (2023).
  3. T-cell repertoire diversity: friend or foe for protective antitumor response? – PMC.
  4. Sonntag, K. et al. Immune monitoring and TCR sequencing of CD4 T cells in a long term responsive patient with metastasized pancreatic ductal carcinoma treated with individualized, neoepitope-derived multipeptide vaccines: a case report. J. Transl. Med. 16, 23 (2018).
  5. Wang, X. et al. T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma. J. Immunother. Cancer 10, e004512 (2022).
  6. Sklavenitis-Pistofidis, R. et al. Immune biomarkers of response to immunotherapy in patients with high-risk smoldering myeloma. Cancer Cell 40, 1358-1373.e8 (2022).
  7. Puig-Saus, C. et al. Neoantigen-targeted CD8+ T cell responses with PD-1 blockade therapy. Nature 615, 697–704 (2023).
  8. Pai, J. A. et al. Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade. Cancer Cell 41, 776-790.e7 (2023).