Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cardinale, Antonella; Compagnucci, Luca; Locatelli, Franco; Velardi, Enrico

doi:10.3389/fimmu.2021.752042

Cited by 17 publications

(14 citation statements)

References 132 publications

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“…Therefore, we conjectured that the predictive value of PTPRD/PTPRT differed between monotherapy and combination therapy, and further exploration is warranted. In this study, PTPRD/PTPRT mutant patients had higher TMB (6), MSI score (8), and TCR score (37), and were positively correlated with ICI treatment. DDR (38) and MMR gene mutations (39), which can increase tumor immunogenicity and promote anti-tumor immunity, were more frequent in the PTPRD/PTPRT mutant cancer patients than in the WT patients.…”

Section: Discussionsupporting

confidence: 48%

“…In this study, PTPRD/PTPRT mutant patients had higher TMB ( 6 ), MSI score ( 8 ), and TCR score ( 37 ), and were positively correlated with ICI treatment. DDR ( 38 ) and MMR gene mutations ( 39 ), which can increase tumor immunogenicity and promote anti-tumor immunity, were more frequent in the PTPRD/PTPRT mutant cancer patients than in the WT patients.…”

Section: Discussionmentioning

confidence: 57%

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PTPRD/PTPRT mutation as a predictive biomarker of immune checkpoint inhibitors across multiple cancer types

Shang

Zhang

et al. 2022

Front. Immunol.

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BackgroundImmune checkpoint inhibitors (ICIs) are dramatically changing the treatment landscape of a variety of cancers. Nevertheless, the variability in ICI responses highlight the importance in identifying predictive biomarkers. PTPRD and PTPRT (PTPRD/PTPRT) are the phosphatases of JAK-STAT signaling, a critical pathway in anti-cancer immunity regulation. However, the pan-cancer association between PTPRD/PTPRT mutation and the efficacy of ICIs remains unclear across pan-cancer patients.MethodsWe analyzed the association between PTPRD/PTPRT mutations and patient outcomes using clinical data and genomic mutations from TCGA pan-cancer cohort. Furthermore, the ICI-treatment cohort was used to evaluate the relationship between PTPRD/PTPRT mutation and the efficacy of ICIs. Another ICIs-treatment cohort was used to validate the findings. The TCGA pan-cancer dataset was analyzed to explore the correlation between PTPRD/PTPRT mutations and immune signatures. Moreover, we combined four factors to construct a nomogram model that could be used to predict the survival of pan-cancer patients receiving ICI treatment. The calibration curves and area under the curve were applied to assess the performance of the model.ResultsPTPRD/PTPRT mutations were shown to be associated with a worse prognosis in TCGA cohort (P < 0.05). In the Samstein cohort, prolonged overall survival (OS) was observed in PTPRD/PTPRT mutant cancers, compared with wild-type cancers (mOS: 40.00 vs 16.00 months, HR = 0.570, 95%CI: 0.479-0.679, P < 0.0001). In the validation cohort, significant OS advantage was observed in PTPRD/PTPRT mutant patients (mOS: 31.32 vs 15.53 months, HR = 0.658, 95%CI: 0.464-0.934, P = 0.0292). Furthermore, PTPRD/PTPRT mutations were associated with a higher tumor mutational burden, MSI score, and TCR score (P < 0.0001). Enhanced immune signatures were found in the PTPRD/PTPRT mutant cancers (P < 0.05). Finally, we successfully established a nomogram model that could be used to predict the survival of NSCLC patients who received ICI treatment. Based on the risk score of the model, patients in the low-risk group showed a better mOS than those in the high-risk group (mOS: 2.75 vs 1.08 years, HR = 0.567, 95%CI: 0.492-0.654; P < 0.001).ConclusionsPTPRD/PTPRT mutations may be a potential biomarker for predicting ICI treatment responsiveness in multiple cancer types.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 57%

PTPRD/PTPRT mutation as a predictive biomarker of immune checkpoint inhibitors across multiple cancer types

Shang

Zhang

et al. 2022

Front. Immunol.

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“…Regarding anti-PD-(L)-1 therapies, some authors have also described an association of higher peripheral diversities at baseline with better outcomes, both using anti-PD-1 [ 117 , 128 , 129 ] and anti-PD-L1 [ 131 ], but the opposite associations have also been reported [ 119 ]. It has also been suggested that the efficacy of ICI therapies may be associated with age, as elderly people present a reduced thymic functionality and a lower peripheral TCR diversity [ 137 ]. This would be in concordance with the idea that more diversified TCR repertoires increase the likelihood of tumour antigens recognition.…”

Section: The Tcr Repertoire As a Predictive Biomarker Of Immune Check...mentioning

confidence: 99%

Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality?

Aran

Garrigós²,

Curigliano

et al. 2022

Cancers

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T cells play a vital role in the anti-tumoural response, and the presence of tumour-infiltrating lymphocytes has shown to be directly correlated with a good prognosis in several cancer types. Nevertheless, some patients presenting tumour-infiltrating lymphocytes do not have favourable outcomes. The TCR determines the specificities of T cells, so the analysis of the TCR repertoire has been recently considered to be a potential biomarker for patients’ progression and response to therapies with immune checkpoint inhibitors. The TCR repertoire is one of the multiple elements comprising the immune system and is conditioned by several factors, including tissue type, tumour mutational burden, and patients’ immunogenetics. Its study is crucial to understanding the anti-tumoural response, how to beneficially modulate the immune response with current or new treatments, and how to better predict the prognosis. Here, we present a critical review including essential studies on TCR repertoire conducted in patients with cancer with the aim to draw the current conclusions and try to elucidate whether it is better to encounter higher clonality with few TCRs at higher frequencies, or higher diversity with many different TCRs at lower frequencies.

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“…Clonal expansion of T cells measured by sequencing TCR beta chains also precedes Ipilimumab toxicity [ 153 ]. Drugs which enhance thymic function and TCR diversity may play a role in improving response rates to ICI [ 154 ].…”

Section: Novel Biomarkers Of Response Resistance and Toxicitymentioning

confidence: 99%

Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise

et al. 2022

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Immune checkpoint inhibitors are monoclonal antibodies that are used to treat over one in three cancer patients. While they have changed the natural history of disease, prolonging life and preserving quality of life, they are highly active in less than 40% of patients, even in the most responsive malignancies such as melanoma, and cause significant autoimmune side effects. Licenced biomarkers include tumour Programmed Death Ligand 1 expression by immunohistochemistry, microsatellite instability, and tumour mutational burden, none of which are particularly sensitive or specific. Emerging tumour and immune tissue biomarkers such as novel immunohistochemistry scores, tumour, stromal and immune cell gene expression profiling, and liquid biomarkers such as systemic inflammatory markers, kynurenine/tryptophan ratio, circulating immune cells, cytokines and DNA are discussed in this review. We also examine the influence of the faecal microbiome on treatment outcome and its use as a biomarker of response and toxicity.

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Thymic Function and T-Cell Receptor Repertoire Diversity: Implications for Patient Response to Checkpoint Blockade Immunotherapy

Cited by 17 publications

References 132 publications

PTPRD/PTPRT mutation as a predictive biomarker of immune checkpoint inhibitors across multiple cancer types

PTPRD/PTPRT mutation as a predictive biomarker of immune checkpoint inhibitors across multiple cancer types

Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality?

Cancer Immunotherapy with Immune Checkpoint Inhibitors-Biomarkers of Response and Toxicity; Current Limitations and Future Promise

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