To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of ROS could dampen antitumor immune responses. In the present study, we demonstrated that IL-15–primed NK cells acquired resistance against oxidative stress through the thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. We show that NK cells residing in the tumor core expressed higher thiol densities that could aid in protecting other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and the NK cell gene signature in tumors may be influenced by tobacco smoking history in patients with non–small-cell lung cancer (NSCLC). Collectively, the levels of reducing antioxidants in NK cells may not only predict better tumor penetrance but potentially even the immune therapy response.

This study aimed to systematically summarize the performance of the machine learning-based radiomics models in the prediction of microsatellite instability (MSI) in patients with colorectal cancer (CRC). It was conducted according to the preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies (PRISMA-DTA) guideline and was registered at the PROSPERO website with an identifier CRD42022295787. Systematic literature searching was conducted in databases of PubMed, Embase, Web of Science, and Cochrane Library up to November 10, 2022. Research which applied radiomics analysis on preoperative CT/MRI/PET-CT images for predicting the MSI status in CRC patients with no history of anti-tumor therapies was eligible. The radiomics quality score (RQS) and Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) were applied to evaluate the research quality (full score 100%). Twelve studies with 4,320 patients were included. All studies were retrospective, and only four had an external validation cohort. The median incidence of MSI was 19% (range 8–34%). The area under the receiver operator curve of the models ranged from 0.78 to 0.96 (median 0.83) in the external validation cohort. The median sensitivity was 0.76 (range 0.32–1.00), and the median specificity was 0.87 (range 0.69–1.00). The median RQS score was 38% (range 14–50%), and half of the studies showed high risk in patient selection as evaluated by QUADAS-2. In conclusion, while radiomics based on pretreatment imaging modalities had a high performance in the prediction of MSI status in CRC, so far it does not appear to be ready for clinical use due to insufficient methodological quality.

Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994-2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at -124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

The prognostic value of albumin-to-alkaline phosphatase ratio (AAPR) in patients with hepatocellular carcinoma (HCC) remains controversial. This meta-analysis aims to evaluate the prognostic role of AAPR in patients with HCC. The databases of Web of Science, Embase, Cochrane Library and PubMed were comprehensively searched from inception to April 25, 2022. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated with Stata 16.0 software for the assessment of the relationship between AAPR and overall survival (OS) as well as recurrence-free survival (RFS) in patients with HCC. A total of 2634 patients from 12 cohorts were included in this meta-analysis. The pooled results showed that lower AAPR predicted poorer OS (HR 2.02, 95% CI 1.78–2.30). Similarly, pooled results demonstrated that lower AAPR also predicted poorer RFS (HR 1.88, 95% CI 1.37–2.57). The heterogeneity for RFS by multivariate analytic results and the publication bias for OS existed, however, the subgroup analysis, meta-regression analysis as well as adjustment using trim-and-fill analysis confirmed an association between AAPR and OS as well as RFS. This meta-analysis proves that lower AAPR in patients with HCC predicted inferior survival outcomes, and AAPR might be a promising indicator for the prognosis of HCC.

Despite the fact that management of EC is moving towards four TCGA-based molecular classifications, a pronounced variation in immune response among these molecular subtypes limits its clinical use. We aimed to investigate the determinant biomarker of ICI response in endometrial cancer (EC). We characterized transcriptome signatures associated with tumor immune microenvironment in EC. Two immune infiltration signatures were identified from the TCGA database (n = 520). The high- and low-infiltration clusters were compared for differences in patient clinical characteristics, genomic features, and immune cell transcription signatures for ICI prediction. A Lasso Cox regression model was applied to construct a prognostic gene signature. Time-dependent receiver operating characteristic curve, Kaplan–Meier curve, nomogram, and decision curve analyses were used to assess the prediction capacity. The efficacy of potential biomarker was validated by the Karolinska endometrial cancer cohort (n = 260). Immune signature profiling suggested that T follicular helper–like cells (Tfh) may be an important and favorable factor for EC; high Tfh infiltration showed potential for clinical use in the anti-PD-1 treatment. A Tfh Infiltration Risk Model (TIRM) established using eight genes was validated, and it outperformed the Immune Infiltration Risk Model. The TIRM had a stable prognostic value in combination with clinical risk factors and could be considered as a valuable tool in a clinical prediction model. We identified CRABP1 as an individual poor prognostic factor in EC. The Tfh-based classification distinguishes immune characteristics and predicts ICI efficacy. A nomogram based on Tfh-related risk score accurately predicted the prognosis of patients with EC, demonstrating superior performance to TCGA-based classification.

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan–Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.