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Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154539 | GEO | 2021/07/13

REPOSITORIES: GEO

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Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer [TCR-Seq]

Project description:As the anti-PD-1 monoclonal antibody (mAb) becomes to be used in many types of cancers, the needs for the predictive biomarker of PD-1 blockade are growing. T cell receptor (TCR) repertoire—which reflects the anti-tumor T-cell responses based on the antigen specificity—is a potential biomarker of cancer immunotherapy. Here, we analyzed the TCR repertoire of patients with advanced gastrointestinal cancer and explored its association with clinical responses.

2021-07-13 | GSE154536 | GEO

Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer[RNA-Seq]

2021-07-13 | GSE154538 | GEO

Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer

Project description:Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer

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Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer [TCR-Seq]

Project description:Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer [TCR-Seq]

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Greater extent of blood-tumor TCR repertoire overlap is associated with favorable clinical responses to PD-1 blockade.

Project description:With the widespread use of programmed death receptor-1 (PD-1) blockade therapy, sensitive and specific predictive biomarkers that guide patient selection are urgently needed. T-cell receptor (TCR) repertoire, which reflects antitumor T-cell responses based on antigen specificity, is expected as a novel biomarker for PD-1 blockade therapy. In the present study, the TCR repertoire of eight patients with gastrointestinal cancer treated with anti-PD-1 antibody (nivolumab) was analyzed. To analyze the tumor-associated T-cell clones in the blood and their mobilization into the tumor, we focused on T-cell clones that presented in both blood and tumor (blood-tumor overlapping clones). Responders to PD-1 blockade tended to exhibit a higher number of overlapping clones in the tumor and a higher total frequency in the blood. Moreover, a higher total frequency of overlapping clones in blood CD8+ T cells before treatment was associated with a favorable clinical response. Collectively, these results suggest the possibility of blood-tumor TCR repertoire overlap to predict clinical response to PD-1 blockade and guide patient selection before the treatment.

| S-EPMC8353913 | biostudies-literature

Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer[RNA-Seq]

Project description:Blood-Tumor overlapping TCR repertoire predicts the clinical responses of PD-1 blockade in patients with gastrointestinal cancer[RNA-Seq]

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Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy

Project description:The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T cell proliferative dysfunctionality could be reverted by PD-1/LAG-3 co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.

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Combined TCR Repertoire Profiles and Blood Cell Phenotypes Predict Melanoma Patient Response to Personalized Neoantigen Therapy plus Anti-PD-1.

Project description:T cells use highly diverse receptors (TCRs) to identify tumor cells presenting neoantigens arising from genetic mutations and establish anti-tumor activity. Immunotherapy harnessing neoantigen-specific T cells to target tumors has emerged as a promising clinical approach. To assess whether a comprehensive peripheral mononuclear blood cell analysis predicts responses to a personalized neoantigen cancer vaccine combined with anti-PD-1 therapy, we characterize the TCR repertoires and T and B cell frequencies in 21 patients with metastatic melanoma who received this regimen. TCR-α/β-chain sequencing reveals that prolonged progression-free survival (PFS) is strongly associated with increased clonal baseline TCR repertoires and longitudinal repertoire stability. Furthermore, the frequencies of antigen-experienced T and B cells in the peripheral blood correlate with repertoire characteristics. Analysis of these baseline immune features enables prediction of PFS following treatment. This method offers a pragmatic clinical approach to assess patients' immune state and to direct therapeutic decision making.

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A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.

Project description:Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.

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Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy.

Project description:The majority of lung cancer patients progressing from conventional therapies are refractory to PD-L1/PD-1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co-expression of PD-1/LAG-3 and were responsive to PD-1 blockade ex vivo and in vivo. In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer-specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co-upregulated PD-1/LAG-3, and were largely refractory to PD-1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T-cell proliferative dysfunctionality could be reverted by PD-1/LAG-3 co-blockade. Patients with functional CD4 immunity and PD-L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD-L1/PD-1 blockade therapy.

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