TCR-seq

TCR-seq / BCR-seq (Immune Repertoire Sequencing)

一行要約

TCR-seq / BCR-seq は T/B 細胞抗原受容体の V(D)J 領域を bulk または single-cell で定量し、clonotype frequency / diversity / convergence / sharing を解析する手法。腫瘍では TIL clonal expansion, IO 応答性予測 (clonal replacement / pre-existing reactivity), neoantigen-specific T 細胞同定, CAR-T persistence, MRD (lymphoid malignancy) 等で活用。Single-cell V(D)J を scRNA-seq / CITE-seq と paired すれば clonotype × phenotype × state を 1 細胞単位で結合できる。

原理

(1) Bulk TCR-seq: gDNA (immunoSEQ) または mRNA (RACE-PCR / multiplex PCR) から CDR3 領域を増幅 → Illumina sequencing → MiXCR / Adaptive pipeline で clonotype 定量。gDNA-based は cell count に直接対応、mRNA-based は発現量補正が必要。(2) Single-cell V(D)J: 10x Chromium 5’ で V(D)J library + GEX library を同 cell barcode 下で取得、cellranger vdj で α/β chain pairing。(3) 解析: Shannon diversity / clonality (1 - Pielou) / Morisita-Horn overlap / GLIPH / TCRdist3 で specificity grouping。

主要エビデンス / 適用領域

• IO 応答 biomarker: pre-treatment TIL TCR clonality と PD-1 blockade 応答の相関 (Riaz et al. Cell 2017); on-treatment の peripheral TCR clonal replacement (Yost et al. NatMed 2019 Nat Med) が再活性化 vs 新規 priming の議論を拓いた
• Neoantigen-specific T 細胞同定: tetramer + scTCR で neoantigen-reactive clonotype を同定、TIL-therapy / TCR-T の標的選定
• CAR-T persistence: insertional barcoding と CAR-specific TCR tracking で in vivo expansion / contraction 動態を追跡
• MRD (lymphoid): B-ALL / DLBCL / MM の患者特異的 V(D)J marker を MRD 高感度モニタリング (clonoSEQ FDA 承認)
• NSCLC TIL: TRACERx / pre-/post-IO biopsy で intratumor heterogeneity と clonotype distribution を mapping

適用分野と限界

• 強み: clonotype 識別の特異性、low-frequency clone (<10⁻⁶) 検出、phenotype × specificity 結合 (single-cell)
• 限界: bulk では α/β pairing 不可、specificity (どの抗原に反応するか) は単独では分からない (tetramer / functional assay 必要)、TCR/peptide 親和性予測 (pMHC binding) の AI モデル (TCRdist / NetTCR / DeepTCR) が validation 段階

Open Questions

• In silico TCR-pMHC binding 予測: HLA / peptide 多様性での generalization
• Single-cell ε-chain (TCR γδ) sequencing の標準化
• Clinical IO 予測 biomarker としての TCR repertoire の prospective validation
• CAR-T 製品の TCR diversity が in vivo expansion / persistence に与える影響

関連エンティティ

• 補完手法: scRNA-seq / CITE-seq / Multiome / Flow-cytometry-CyTOF
• 関連細胞: CD8-T-cell / Exhausted-CD8-T-cell / Tpex / CAR-T-cell / B-cell / Plasma-cell
• 関連薬剤: PD-1-inhibitor / CAR-T-therapy / TCR-T-therapy / TIL-therapy
• 関連概念: T-cell-exhaustion / MRD-ctDNA-monitoring / Tumor-mutational-burden

関連論文

直近 30 件のみ表示中 (関連 53 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Biermann et al. Cell 2022 — Dissecting the treatment-naive ecosystem of human melanoma brain metastasis
• Tagore et al. NatMed 2025 — Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases

Basic-Immunotherapy

• Koya et al. BloodCancerDiscov 2021 — Single-cell analysis of the multicellular ecosystem in viral carcinogenesis by HTLV-1
• Liu et al. CancerCell 2026 — Clonal lineage tracing of innate immune cells in human cancer
• George et al. CancerRes 2026 — Immune checkpoint blockade augments lymphodepleting chemotherapy-induced antitumor immunity by expanding effector CD8…
• Buggert et al. Cell 2020 — The identity of human tissue-emigrant CD8+ T cells
• Burger et al. Cell 2021 — Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors
• Luoma et al. Cell 2022 — Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy
• Malekzadeh et al. ClinCancerRes 2020 — Antigen experienced T cells from peripheral blood recognize p53 neoantigens
• Virtakoivu et al. ClinCancerRes 2021 — Systemic blockade of clever-1 elicits lymphocyte activation alongside checkpoint molecule downregulation in patients
• Bilate et al. Immunity 2020 — T cell receptor is required for differentiation, but not maintenance, of intestinal CD4+ intraepithelial lymphocytes
• Reuben et al. NatCommun 2020 — Comprehensive T cell repertoire characterization of non-small cell lung cancer
• Ito et al. NatCommun 2026 — Phenotype of circulating tumor-reactive t cells predicts immune checkpoint inhibitor response in non-small cell lung
• Ravi et al. NatGenet 2023 — Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
• Lee et al. NatImmunol 2022 — Significance of bystander T cell activation in microbial infection
• Gonzalez-Kozlova et al. NatMed 2026 — Humoral IgG1 responses to tumor antigens underpin clinical outcomes in immune checkpoint blockade
• Caushi et al. Nature 2021 — Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers
• Han et al. SciAdv 2021 — Weighting tumor-specific TCR repertoires as a classifier to stratify the immunotherapy delivery in non-small cell lung
• Foord et al. SciTranslMed 2021 — Characterization of ascites-and tumor-infiltrating gammadelta T cells reveals distinct repertoires and a beneficial
• Zheng et al. Science 2021 — Pan-cancer single-cell landscape of tumor-infiltrating T cells

Basic-Neutrophil and myeloid cell

• Cheng et al. Cell 2021 — A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells

Basic-Oncogene and genetics

• Leader et al. CancerCell 2021 — Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification

Basic-Others

• Gfeller et al. NatCancer 2026 — Advances in predicting t cell epitope recognition for cancer immunotherapy

Clinical-Mesothelioma

• Vroman et al. JImmunotherCancer 2020 — T cell receptor repertoire characteristics both before and following immunotherapy correlate with clinical response in

Clinical-NSCLC-Driver negative

• Willmann et al. JClinOncol 2026 — Metastatic trajectories in non-small cell lung cancer guide local and systemic therapies

Clinical-Novel modalities

• Creelan et al. NatMed 2021 — Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer a phase 1 trial
• Hu et al. NatMed 2021 — Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma

Clinical-Others

• Poussaint et al. ClinCancerRes 2026 — And young adult patients with recurrent CNS tumors and newly-diagnosed DIPG

Clinical-SCLC

• Lai et al. JImmunotherCancer 2020 — CDK46 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in

Clinical-Thymic

• Caruso et al. TrendsCancer 2023 — Thymic expression of immune checkpoint molecules and their implication for response to immunotherapies