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Time-spatial analysis of T cell receptor repertoire in esophageal squamous cell carcinoma patients treated with combined radiotherapy and PD-1 blockade.

ABSTRACT: T cell receptor (TCR) repertoire as a biomarker for predicting immunotherapy efficiency has been widely studied. However, its dynamics during radiotherapy combined with PD-1 blockade is little known. Using paired tumor and blood samples from the phase Ib clinical study (NCT03222440), we investigate the time-spatial TCR repertoire in esophageal squamous cell carcinoma (ESCC) patients treated with first-line definitive radiotherapy concurrently with anti-PD-1 antibody camrelizumab, and also evaluate the association between TCR repertoire and clinical outcomes. TCR sequencing was performed on tumor biopsies (n = 34, 15 pairs) and peripheral CD8⁺ T cells (n = 36, 18 pairs) collected at baseline and during treatment (after 40 Gy radiation and 2 rounds of camrelizumab). Whole exome sequencing was applied to estimate genomic mutations and tumor mutation burden. We show that the intratumoral TCR repertoire at baseline was correlated with tumor microenvironment and presented heterogeneity inter-individually. T-cell clones inflowed mutually between tumors and peripheral blood under combination treatment, resulting in an elevation of intratumoral TCR diversity. The peripheral CD8⁺ TCR diversity at baseline, increased tumor-peripheral Morisita-Horn overlap during treatment, and expansion of persistent intratumoral T-cell clones during treatment predicted improved survival. While it is unclear whether radiation contributed to the TCR changes versus PD-1 therapy alone, our results firstly reveal radiotherapy combined with PD-1 blockade greatly promoted time-spatial alteration of TCR repertoire between tumor and peripheral blood, which demonstrate the peripheral CD8⁺ TCR diversity at baseline and dynamic alteration of intratumoral TCRs acted as potential effective biomarkers of radiotherapy combined with immunotherapy in ESCC.

SUBMITTER: Yan C

PROVIDER: S-EPMC8759588 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe first clinical study (NCT03671265) of first-line chemoradiotherapy combined with PD-1 blockade showed promising treatment outcomes in locally advanced esophageal squamous cell carcinoma (ESCC). However, partial patients did not respond to the combination treatment. The roles of dendritic cells (DCs) and macrophages in this combination treatment remain poorly understood.MethodsWe performed multiplexed immunofluorescence method to identify CD11c+ DCs, CD68+ macrophages, and their PD-L1- or PD-L1+ subpopulations in paired tumor biopsies (n = 36) collected at baseline and during the combination treatment (after radiation, 40 Gy) from the phase Ib trial (NCT03671265). We applied whole exome sequencing in the baseline tumor biopsies (n = 14) to estimate tumor mutation burden (TMB). We dynamically investigated the spatial distribution of DCs and macrophages under chemoradiotherapy combined with PD-1 blockade, and evaluated the association between their spatial distribution and combination outcome, and TMB.ResultsThe results showed that high percentages of PD-L1- DCs and macrophages in the baseline tumor compartment, but not in the stromal compartment, predicted improved OS and PFS. Chemoradiotherapy combined with PD-1 blockade promoted DCs and macrophages to migrate closer to tumor cells. During combination treatment, PD-L1- tumor cells were nearest to PD-L1- DCs and macrophages, while PD-L1+ tumor cells were next to PD-L1+ DCs and macrophages. High TMB was closely associated with a shorter distance from tumor cells to DCs and macrophages. Shorter distance between PD-L1+ tumor cells and PD-L1+ DCs or PD-L1- macrophages during the combination was correlated with better OS. Shorter distance between PD-L1- tumor cells and PD-L1- macrophages during combination was associated with both longer OS and PFS.ConclusionsPD-L1- or PD-L1+ DCs and macrophages exhibit distinct spatial distribution in ESCC. The close distance between tumor cells and these antigen-presenting cells (APCs) is critical to the clinical outcome in chemoradiotherapy combined with PD-1 blockade in ESCC patients. Our results highlight the predictive potential of spatial patterns of APCs in chemoradiotherapy combined with immunotherapy and reveal the underlying mechanism of APCs participating in chemoradiotherapy-induced antitumor immune response in ESCC.

Project description:BackgroundOnly a fraction of patients with esophageal squamous cell carcinoma (ESCC) show tumor responses to anti-programmed cell death protein 1 (PD-1) therapy. The predictive value of single biomarkers for prognosis is limited, and a more comprehensive approach that incorporates multiple factors may improve the prognostic prediction. Here, we conducted a retrospective study to develop a combined immune prognostic index (CIPI) for predicting clinical outcomes of ESCC patients treated with anti-PD-1 therapy.Design and methodsWe performed a pooled analysis of two multicenter clinical trials comparing immunotherapy versus chemotherapy as second-line treatment in ESCC patients. The discovery cohort comprised patients who received anti-PD-1 inhibitors (N = 322) and the control cohort comprised patients who received chemotherapy (N = 307). The validation cohort included patients with pan-cancers treated with PD-1/programmed cell death ligand-1 inhibitors, except for ESCC (N = 110). Multivariable Cox proportional hazard regression was used to assess the prediction value of variables on survival.ResultsIn the discovery cohort, neutrophil-to-lymphocyte ratio, serum albumin, and liver metastasis were independently associated with overall survival (OS) and progression-free survival (PFS). We integrated the three variables into CIPI and found that CIPI could categorize patients into four subgroups (CIPI 0 to CIPI 3) with distinct OS, PFS, and tumor responses. The CIPI was also predictive of clinical outcomes in the validation cohort, but not in the control cohort. Furthermore, patients with CIPI 0, CIPI 1, and CIPI 2 were more likely to benefit from anti-PD-1 monotherapy than chemotherapy, while patients with CIPI 3 did not benefit from anti-PD-1 monotherapy over chemotherapy.ConclusionsThe CIPI score was a robust biomarker for prognostic prediction in ESCC patients treated with anti-PD-1 therapy and was immunotherapy specific. The CIPI score may also be applicable for prognostic prediction in pan-cancers.

Project description:The tumor immune response is dependent on the interaction between tumor cells and the T-cell subset expressing the T-cell receptor (TCR) repertoire that infiltrates into the tumor microenvironment. The present study explored the diversity and shared TCR repertoires expressed on the surface of locoregional T cells and identified the T lymphocyte subsets infiltrating into esophageal squamous cell carcinoma (ESCC), in order to provide insight into the efficiency of immunotherapy and the development of a novel immune-oriented therapeutic strategy. A total of 53 patients with ESCC were enrolled in the present study, and immunohistochemical analysis of CD3, CD8, CD45RO, FOXP3, CD274, HLA class I and AE1/AE3 was performed. Digital pathological assessment was performed to evaluate the expression level of each marker. The clinicopathological significance of the immuno relation high (IR-Hi) group was assessed. Adaptor ligation PCR and next-generation sequencing were performed to explore the diversity of the TCR repertoire and to investigate the shared TCR repertoire in the IR-Hi group. Repertoire dissimilarity index (RDI) analysis was performed to assess the diversity of TCR, and the existence of shared TCRα and TCRβ was also investigated. Further stratification was performed according to the expression of markers of different T-cell subsets. Patients were stratified into IR-Hi and immuno relation low (IR-Lo) groups. Cancer-specific survival and recurrence-free survival rates were significantly improved in the IR-Hi group compared with in the IT-Lo group. The diversity of the TCR repertoire was significantly higher in the IR-Hi group. TCR repertoire analysis revealed 27 combinations of TCRα and 23 combinations of TCRβ VJ regions that were shared among the IR-Hi group. The IR-Hi group was divided into three clusters. Overall, the current findings revealed that the IR-Hi group maintained the diversity of TCR, and a portion of the IR-Hi cases held the T cells with shared TCR repertoires, implying recognition of shared antigens. The prognosis of patients with ESCC was affected by the existence of immune response cells and may possibly be stratified by the T-cell subsets.

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Time-spatial analysis of T cell receptor repertoire in esophageal squamous cell carcinoma patients treated with combined radiotherapy and PD-1 blockade.

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