Immune-active tumor-adjacent tissues are associated with favorable prognosis in stage I lung squamous cell carcinoma.

The immunogenomic features of tumor-adjacent lungs (TALs) in stage I lung squamous cell carcinoma (LUSC) are not clear. Multiomics analyses of tumor tissues and paired TALs from 59 stage I LUSC patients were performed. Compared to tumors, TALs exhibited a better-preserved immune contexture indicated by upregulation of immune pathways, increased immune infiltration, and higher expression of immune effector molecules. Notably, TALs had no mutations in PTEN and KEAP1, a lower incidence of human leukocyte antigen (HLA) loss and higher expression of HLA class I genes, major histocompatibility complex (MHC) I chaperones, and interferon (IFN)-γ-associated genes. Digital spatial profiling validated the generally higher immune infiltration in TALs and revealed a higher level of immune heterogeneity in LUSC tumors. Importantly, patients with higher immune infiltration in TALs had significantly longer survival, while high immune heterogeneity was associated with inferior patient survival. Our work can be considered in the selection of patients for adjuvant therapy, especially immunotherapy.

Genomic and TCR profiling data reveal the distinct molecular traits in epithelial ovarian cancer histotypes.

Epithelial ovarian cancer (EOC) is classified into five major histotypes: high-grade serous (HGSOC), low-grade serous (LGSOC), clear cell (CCOC), endometrioid (ENOC), and mucinous (MOC). However, the landscape of molecular and immunological alterations in these histotypes, especially LGSOC, CCOC, ENOC, and MOC, is largely uncharacterized. We collected 101 treatment-naive EOC patients. The resected tumor tissues and paired preoperative peripheral blood samples were collected and subjected to target sequencing of 1021 cancer-associated genes and T cell repertoire sequencing. Distinct characteristics of mutations were identified among the five histotypes. Furthermore, tumor mutation burden (TMB) was found to be higher in CCOC and ENOC, but lower in LGSOC and HGSOC. Alterations associated with DNA damage repair (DDR) pathways and homologous recombination deficiencies (HRD) were prevalent in five histotypes. CCOC demonstrated increased level of T cell clonality compared with HSGOC. Interestingly, the proportion of the 100 most common T cell clones was associated with TMB and tumor neoantigen burden in CCOC, highlighting more sensitive anti-tumor responses in this histotype, which was also evidenced by the enhanced convergent recombination of T cell clones. These findings shed light on the molecular traits of genomic alteration and T cell repertoire in the five major EOC histotypes and may help optimize clinical management of EOC with different histotypes.

Lung cancer-associated T cell repertoire as potential biomarker for early detection of stage I lung cancer.

BACKGROUND: Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer. METHODS: Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs). RESULTS: A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96). CONCLUSION: This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Rationale: Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. Objectives: To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. Methods: We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. Measurements and Main Results: GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Conclusions: Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).

Circulating tumor DNA by high-throughput sequencing of T cell receptor monitored treatment response and predicted treatment failure in T cell lymphomas.

INTRODUCTION: Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. Studies for T cell lymphoma are limited. METHODS: We explored whether this technology is applicable to T cell lymphoma with different subtypes and assessed its performance in clinical settings. RESULTS: Thirty tumor and 74 blood samples were analyzed in our study. Malignant clone was identified in 23 of the 30 (76.7%) tumor samples through high-throughput sequencing (HTS) combined with PCR. We detected the same tumor clone in plasma in 18out of the 23 (78.3%) patients. Circulating tumor DNA fraction correlated with lactate dehydrogenase (LDH) (r = .52, P = .017), high level of ctDNA predicted treatment failure (P = .0003) and there was a trend patients with high ctDNA burden would have poorer PFS Furthermore, ctDNA changed in concordance with clinical outcome and was more sensitive than PET/CT. Also, recurrence of ctDNA was an important clue for relapse. CONCLUSION: In conclusion, our study indicated that ctDNA monitoring was suitable for T cell lymphoma. High level of pretreatment ctDNA was a poor prognosis factor and changes of ctDNA correlated well with clinical courses and was sensitive to find early relapse.

TCR-Seq Identifies Distinct Repertoires of Distant-Metastatic and Nondistant-Metastatic Thyroid Tumors.

CONTEXT: Malignant thyroid tumor with distant metastasis is associated with poor outcome. Early detection of distant metastasis is of great clinical importance. OBJECTIVE: Thyroid tumor infiltrated with T cells can serve as a biomarker for monitoring metastasis. DESIGN: A retrospective analysis was performed of patient clinical samples collected between 2012 to 2018, using T-cell receptor sequencing (TCR-seq) for clinical exploration. SETTING: This study took place at Zhejiang Cancer Hospital. PATIENTS: Sixty-eight patients with papillary thyroid cancer (PTC) (distinct metastatic status) and 21 patients with benign nodules were enrolled. All patients had not received any treatment before surgery. MAIN OUTCOME MEASURE: The characteristics of TCRß complementary-determining region 3 (CDR3) for each patient were determined by high-throughput sequencing. RESULTS: The TCRß diversity of malignant tumors is significantly higher than benign nodules both in blood and tumor samples (Shannon index, blood, P < .01; tumor, P < .001). The malignant tumors with distant metastasis or invasiveness showed lower TCRß diversity than nonmetastasis (Shannon index, P < .01) or noninvasive (Shannon index, P < .01) malignant tumors. Analysis of the Morisita-Horn similarity index indicated significant TCRß repertoire similarity between tumor and blood in distant-metastatic patients (comparison with nonmetastasis, P < .05). According to the discrepancy of the CDR3 among patients with different clinicopathological status, the classifier was constructed to discriminate distant-metastatic individuals. A promising area under the curve value of 83.8% was obtained with the number of overlapping CDR3 clonotypes. CONCLUSION: The availability and reliability of TCR-seq render it prospective to translate these intrinsic attributes into clinical practice for monitoring distant metastasis in PTC patients.