CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire

Robert, Lídia; Tsoi, Jennifer; Wang, Xiaoyan; Emerson, Ryan; Homet, Blanca; Chodon, Thinle; Mok, Stephen; Huang, Rong; Cochran, Alistair J.; Comin-Anduix, Begoñya; Koya, Richard C.; Graeber, Thomas G.; Robins, Harlan; Ribas, Antoni

doi:10.1158/1078-0432.ccr-13-2648

Cited by 328 publications

(217 citation statements)

References 41 publications

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“…Conversely, a diverse TCR repertoire consisting of fewer highly expanded T-cell clones, which is known to be a hallmark of robust anti-viral T-cell immunity, might enhance broad tumor antigen control, thus making immune escape less likely (8)(9)(10). Consistent with this notion, it is known that subdominant T-cell clones can potentially target neo-antigens (6). In DLBCL, it is possible that smaller T-cell clones are more important to response once the effective chemotherapy regimen has significantly debulked the initial tumor load.…”

Section: Discussionmentioning

confidence: 95%

“…However, there is a limited assessment of the impact of the T-cell receptor (TCR) repertoires of intra-tumoral T cells on outcome in cancer. There have been several studies examining the dynamics of the TCR repertoire after treatment with immune checkpoint inhibitors (6,7). Conversely, there are minimal data on the impact of the TCR repertoire on survival after conventional (i.e., non-checkpoint targeting) multi-agent therapy in solid tumors or lymphomas.…”

Section: Introductionmentioning

confidence: 99%

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The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Keane

Gould

Jones

et al. 2017

Clinical Cancer Research

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Purpose: To investigate the relationship between the intratumoral T-cell receptor (TCR) repertoire and the tumor microenvironment (TME) in de novo diffuse large B-cell lymphoma (DLBCL) and the impact of TCR on survival.Experimental Design: We performed high-throughput unbiased TCRb sequencing on a population-based cohort of 92 patients with DLBCL treated with conventional (i.e., non-checkpoint blockade) frontline "R-CHOP" therapy. Key immune checkpoint genes within the TME were digitally quantified by nanoString. The primary endpoints were 4-year overall survival (OS) and progression-free survival (PFS).Results: The TCR repertoire within DLBCL nodes was abnormally narrow relative to non-diseased nodal tissues (P < 0.0001). In DLBCL, a highly dominant single T-cell clone was associated with inferior 4-year OS rate of 60.0% [95% confidence interval (CI), 31.7%-79.6%], compared with 79.8% in patients with a low dominant clone (95% CI, 66.7%-88.5%; P ¼ 0.005). A highly dominant clone also predicted inferior 4-year PFS rate of 46.6% (95% CI, 22.5%-76.6%) versus 72.6% (95% CI, 58.8%-82.4%, P ¼ 0.008) for a low dominant clone. In keeping, clonal expansions were most pronounced in the EBV þ DLBCL subtype that is known to express immunogenic viral antigens and is associated with particularly poor outcome. Increased T-cell diversity was associated with significantly elevated PD-1, PD-L1, and PD-L2 immune checkpoint molecules. Conclusions: Put together, these findings suggest that the TCR repertoire is a key determinant of the TME. Highly dominant T-cell clonal expansions within the TME are associated with poor outcome in DLBCL treated with conventional frontline therapy.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

Keane

Gould

Jones

et al. 2017

Clinical Cancer Research

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“…39 Recently, effects of CTLA-4 blockade on the TCR repertoire in peripheral blood have been investigated. 40 Robert and colleagues reported a diversification of the peripheral T cell pool after treatment with CTLA-4 blocking antibody (tremelimumab) in contrast to healthy donor PBMC. Similar to anti-CTLA-4 therapy, treatment with cetuximab enhances anti-tumor immunity in a subset of patients.…”

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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“…The numbers of unique CDR3s and lineages were used as a measure to evaluate the clonal diversity of the B cell repertoire (16,21). A unique CDR3 clone whose reads account for .0.1% of total reads stands for a "highly expressed clone" (HEC-unique CDR3) (22).…”

Section: Reduced Clonal Diversity and Enhanced Clonal Expansion And Ementioning

confidence: 99%

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis

Tan

Wang

Zhang

et al. 2016

The Journal of Immunology

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Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by elevated serum anti-mitochondrial Ab and lymphocyte-mediated bile duct damage. This study was designed to reveal the clonal characteristics of B lymphocyte repertoire in patients with PBC to facilitate better understanding of its pathogenesis and better management of these patients. Using high-throughput sequencing of Ig genes, we analyzed the repertoire of circulating B lymphocytes in 43 patients with PBC, and 34 age- and gender-matched healthy controls. Compared with healthy controls, PBC patients showed 1) a gain of 14 new clones and a loss of 8 clones; 2) a significant clonal expansion and increased relative IgM abundance, which corresponded with the elevated serum IgM level; 3) a significant reduction of clonal diversity and somatic hypermutations in class-switched sequences, which suggested a general immunocompromised status; 4) the reduction of clonal diversity and enhancement of clonal expansion were more obvious at the cirrhotic stage; and 5) treatment with ursodeoxycholic acid could increase the clonal diversity and reduce clonal expansion of the IgM repertoire, with no obvious effect on the somatic hypermutation level. Our data suggest that PBC is a complex autoimmune disease process with evidence of B lymphocyte clonal gains and losses, Ag-dependent ogligoclonal expansion, and a generally compromised immune reserve. This new insight into the pathogenesis of PBC opens up the prospect of studying disease-relevant B cells to better diagnose and treat this devastating disease.

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CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire

Cited by 328 publications

References 41 publications

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma

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

Clonal Characteristics of Circulating B Lymphocyte Repertoire in Primary Biliary Cholangitis

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