Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation

Heijst, Jeroen W. J. van; Ceberio, Izaskun; Lipuma, Lauren; Samilo, Dane; Wasilewski, Gloria; Gonzales, Anne Marie; Nieves, Jimmy; Brink, Marcel R.M. van den; Perales, Miguel Angel; Pamer, Eric G.

doi:10.1038/nm.3100

Cited by 182 publications

(184 citation statements)

References 39 publications

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“…Van Heijst and colleagues report consistent findings of patient groups with increased TCR diversity and decreased risk of infection and cancer relapse. 32 In patients following septic shock, TCR diversity is reduced and normalization of TCR diversity and PD-1 expression was reported to positively correlate with survival. 33 In patients with hepatitis C virus (HCV) infection, Miles and colleagues observed that TCR repertoire diversity is associated with HCV clearance.…”

Section: Discussionmentioning

confidence: 99%

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

et al. 2018

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The role of T cell receptor (TCR) signaling for adaptive immune responses is essential. The ability to respond to a broad spectrum of tumor antigens requires an adaptive selection of various TCR. So far, little is known about the role of TCR richness and clonality in the cellular immune response to head and neck cancer (HNC), though the Endothelial Growth Factor Receptor (EGFR)-specific CD8+ T cell response can be enhanced by cetuximab therapy. Therefore, we investigated differences in TCR sequences between human papillomavirus (HPV)+ and HPV− HNC patients, as well as differences in TCR sequence characteristics between T cells of peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL). Additionally, we were able to investigate the TCR richness and clonality in samples pre- and post- treatment in a prospective clinical trial of neoadjuvant cetuximab. Interestingly, HPV+ and HPV− HNSCC did not significantly differ in the extent of TCR clonality and richness in PBMC or TIL. However, neoadjuvant cetuximab treatment increased the number of unique TCR sequences in PBMC (p = 0.0003), which was more prominent in the clinical responder patients compared to non-responders (p = 0.04). A trend toward TCR gene focusing was observed in TIL (p = 0.1) post-treatment. Thus, an increase in richness of TCR sequences in the periphery with a focusing at the tumor site is associated with an improved treatment response, suggesting an influence of peripheral quantity and intratumoral quality on adaptive immunity in cetuximab treated patients.

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Section: Discussionmentioning

confidence: 99%

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

et al. 2018

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“…DUCB recipients had a lower incidence of infection, higher CD4 C T cell numbers and a reduced rate of leukemia relapse compared with TCD recipients. 8 Muraro et al reported that CD4 C T and CD8 C T TCR diversity in response patients was increased compared with non-response patients before and after haematopoietic stem cell transplantation. 9 Jia et al reported that high NSDE of the mucosal T cell repertoire in gastric cancer correlates with patient short-term and overall survival time.…”

Section: Discussionmentioning

confidence: 99%

“…7 TCR diversity is closely related to treatment effectiveness and patient prognosis in different diseases. [8][9][10][11] The analysis of TCR diversity in diseases might also facilitate the elucidation of pathogenesis and the development of cellular immunotherapy approaches that target specific tumors and neoantigens. 12,13 Although tumor-infiltrating T lymphocytes have implications for tumor prognosis, information on the TCR diversity of HBV-associated liver cancer remains limited.…”

Section: Introductionmentioning

confidence: 99%

High-throughput T cell receptor sequencing reveals distinct repertoires between tumor and adjacent non-tumor tissues in HBV-associated HCC

Chen

Zhao

et al. 2016

OncoImmunology

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T lymphocytes, which recognize antigen peptides through specific T cell receptors (TCRs), play an important role in the human adaptive immune response. TCR diversity is closely associated with host immune response and cancer prognosis. Although tumor-infiltrating T lymphocytes have implications for tumor prognosis, few studies have performed a detailed characterization of TCR diversity in both tumor and non-tumor tissues in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Here, we performed high-throughput sequencing of the TCRb chain complementarity determining region 3 (CDR3) of liver-infiltrating T cells from 48 HBV-associated HCC patients. A significantly higher average number of CDR3 aa clonotypes (2259 vs. 1324, p < 0.001), and significantly higher TCR diversity (Gini coefficient, p < 0.001; Simpson index, p < 0.01; Shannon entropy, p < 0.001) were observed in tumor tissues compared with adjacent non-tumor tissues. The ratio of highly expanded clones (HECs) was significantly higher in non-tumor tissues than in tumor tissues when the HEC threshold was defined as 2% or greater (p < 0.05). Our analysis of the median Morisita-Horn index indicated weak TCR repertoire similarity between tumor and matched non-tumor tissues. The median number of shared clones in tumor tissue and matched non-tumor tissue from each patient was 360.5, representing 5.1-15.8% (10.6 § 0.4%) of all clones in each patient. We observed extensive heterogeneity of T lymphocytes in tumors and higher HEC ratios in adjacent non-tumor tissues of HCC patients. The differential T cell repertoires in tumor and non-tumor tissues suggest a distinct T cell immune microenvironment in patients with HBV-associated HCC.

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“…37,38 Briefly, total RNA was extracted and TRB gene products were amplified through 5' rapid amplification of cDNA ends (RACE) PCR (Clontech, Palo Alto, CA, USA) followed by sequencing with Roche 454 sequencer (Roche, Basel, Switzerland).…”

Section: Pcr Specific For the Tcrmentioning

confidence: 99%

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection

Hanajiri

Murata

Sugimoto

et al. 2015

Bone Marrow Transplant

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In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8 + T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.

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Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation

Cited by 182 publications

References 39 publications

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

High-throughput T cell receptor sequencing reveals distinct repertoires between tumor and adjacent non-tumor tissues in HBV-associated HCC

Integration of humoral and cellular HLA-specific immune responses in cord blood allograft rejection

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