Thermo-immune synergy: Camrelizumab plus microwave ablation in preoperative early-stage breast cancer.

Immunotherapy has enhanced breast cancer outcomes, but optimizing combination therapies is crucial. Integrating additional treatment modalities, like physical therapies, holds promise for optimizing efficacy. Pan et al. recently reported that combining preoperative immunotherapy with microwave ablation is safe and feasible in early-stage breast cancer, effectively sensitizing peripheral CD8+ T cells.1.

Inference of Gene Regulatory Networks Based on Multi-view Hierarchical Hypergraphs.

Since gene regulation is a complex process in which multiple genes act simultaneously, accurately inferring gene regulatory networks (GRNs) is a long-standing challenge in systems biology. Although graph neural networks can formally describe intricate gene expression mechanisms, current GRN inference methods based on graph learning regard only transcription factor (TF)-target gene interactions as pairwise relationships, and cannot model the many-to-many high-order regulatory patterns that prevail among genes. Moreover, these methods often rely on limited prior regulatory knowledge, ignoring the structural information of GRNs in gene expression profiles. Therefore, we propose a multi-view hierarchical hypergraphs GRN (MHHGRN) inference model. Specifically, multiple heterogeneous biological information is integrated to construct multi-view hierarchical hypergraphs of TFs and target genes, using hypergraph convolution networks to model higher order complex regulatory relationships. Meanwhile, the coupled information diffusion mechanism and the cross-domain messaging mechanism facilitate the information sharing between genes to optimise gene embedding representations. Finally, a unique channel attention mechanism is used to adaptively learn feature representations from multiple views for GRN inference. Experimental results show that MHHGRN achieves better results than the baseline methods on the E. coli and S. cerevisiae benchmark datasets of the DREAM5 challenge, and it has excellent cross-species generalization, achieving comparable or better performance on scRNA-seq datasets from five mouse and two human cell lines.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PICOTEES: a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants from Chinese children cohorts.

The growth in biomedical data resources has raised potential privacy concerns and risks of genetic information leakage. For instance, exome sequencing aids clinical decisions by comparing data through web services, but it requires significant trust between users and providers. To alleviate privacy concerns, the most commonly used strategy is to anonymize sensitive data. Unfortunately, studies have shown that anonymization is insufficient to protect against reidentification attacks. Recently, privacy-preserving technologies have been applied to preserve application utility while protecting the privacy of biomedical data. We present the PICOTEES framework, a privacy-preserving online service of phenotype exploration for genetic-diagnostic variants (https://birthdefectlab.cn:3000/). PICOTEES enables privacy-preserving queries of the phenotype spectrum for a single variant by utilizing trusted execution environment technology, which can protect the privacy of the user's query information, backend models, and data, as well as the final results. We demonstrate the utility and performance of PICOTEES by exploring a bioinformatics dataset. The dataset is from a cohort containing 20,909 genetic testing patients with 3,152,508 variants from the Children's Hospital of Fudan University in China, dominated by the Chinese Han population (>99.9%). Our query results yield a large number of unreported diagnostic variants and previously reported pathogenicity.

Comprehensive genomic profiling of breast cancers characterizes germline-somatic mutation interactions mediating therapeutic vulnerabilities.

Germline-somatic mutation interactions are universal and associated with tumorigenesis, but their role in breast cancer, especially in non-Caucasians, remains poorly characterized. We performed large-scale prospective targeted sequencing of matched tumor-blood samples from 4079 Chinese females, coupled with detailed clinical annotation, to map interactions between germline and somatic alterations. We discovered 368 pathogenic germline variants and identified 5 breast cancer DNA repair-associated genes (BCDGs; BRCA1/BRCA2/CHEK2/PALB2/TP53). BCDG mutation carriers, especially those with two-hit inactivation, demonstrated younger onset, higher tumor mutation burden, and greater clinical benefits from platinum drugs, PARP inhibitors, and immune checkpoint inhibitors. Furthermore, we leveraged a multiomics cohort to reveal that clinical benefits derived from two-hit events are associated with increased genome instability and an immune-activated tumor microenvironment. We also established an ethnicity-specific tool to predict BCDG mutation and two-hit status for genetic evaluation and therapeutic decisions. Overall, this study leveraged the large sequencing cohort of Chinese breast cancers, optimizing genomics-guided selection of DNA damaging-targeted therapy and immunotherapy within a broader population.

Ipsilateral breast tumor recurrence after breast-conserving surgery: insights into biology and treatment.

Despite modern surgical and irradiation techniques, ipsilateral breast tumor recurrence (IBTR) accounts for 5-15% of all cancer recurrence in women treated with breast conservative treatment. Historically, this event has been treated definitively with salvage mastectomy and completion axillary clearance. However, many local recurrences are small and without nodal involvement at presentation. Thus, there has been an interest in performing a surgical de-escalation procedure in the breast and the axilla. The current guidelines do not provide detailed descriptions and treatment suggestions for these selected patients, resulting in inconsistent treatment strategies. Moreover, the methods to define true recurrence (TR) and new primary tumor (NP) for IBTR remain controversial. Most developed classification methods mainly rely on clinical and pathological criteria, limiting the accuracy of the discerption and causing misclassification. In this editorial, we will discuss the current trends in surgical de-escalation for patients with IBTR. Moreover, we will focus on recent IBTR innovations, highlighting molecular-integrated classification and multimodal staging methods for clinical practice and postoperative surveillance strategies.

Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer.

The molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody‒drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor-negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor-negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor-positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype.

CCL19+ dendritic cells potentiate clinical benefit of anti-PD-(L)1 immunotherapy in triple-negative breast cancer.

BACKGROUND: The extensive involvement of dendritic cells (DCs) in immune contexture indicates their potent value in cancer immunotherapy. Understanding DC diversity in patient cohorts may strengthen the clinical benefit of immune checkpoint inhibitors (ICIs). METHODS: Single-cell profiling of breast tumors from two clinical trials was performed to investigate DC heterogeneity. Multiomics, tissue characterization, and pre-clinical experiments were used to evaluate the role of the identified DCs in the tumor microenvironment. Four independent clinical trials were leveraged to explore biomarkers to predict ICI and chemotherapy outcomes. FINDINGS: We identified a distinct CCL19-expressing functional state of DCs associated with favorable responses to anti-programmed death (ligand)-1 (PD-(L)1), which displayed migratory and immunomodulatory phenotypes. These cells were correlated with antitumor T cell immunity and the presence of tertiary lymphoid structures and lymphoid aggregates, defining immunogenic microenvironments in triple-negative breast cancer. In vivo, CCL19+ DC deletion by Ccl19 gene ablation dampened CCR7+CD8+ T cells and tumor elimination in response to anti-PD-1. Notably, high circulating and intratumoral CCL19 levels were associated with superior response and survival in patients receiving anti-PD-1 but not chemotherapy. CONCLUSIONS: We uncovered a critical role of DC subsets in immunotherapy, which has implications for designing novel therapies and patient stratification strategies. FUNDING: This study was funded by the National Key Research and Development Project of China, the National Natural Science Foundation of China, the Program of Shanghai Academic/Technology Research Leader, the Natural Science Foundation of Shanghai, the Shanghai Key Laboratory of Breast Cancer, the Shanghai Hospital Development Center (SHDC), and the Shanghai Health Commission.

Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: The FUTURE phase II umbrella clinical trial.

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4-38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7-4.2) and 10.7 (95% CI: 9.1-12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody-drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

Famitinib with Camrelizumab and Nab-Paclitaxel for Advanced Immunomodulatory Triple-Negative Breast Cancer (FUTURE-C-Plus): An Open-Label, Single-Arm, Phase II Trial.

PURPOSE: Camrelizumab, an mAb against programmed cell death protein 1 (PD-1), plus nab-paclitaxel exhibited promising antitumor activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC). Famitinib is a tyrosine kinase inhibitor targeting VEGFR2, PDGFR, and c-kit. We aimed to assess the efficacy and safety of a novel combination of famitinib, camrelizumab, and nab-paclitaxel in advanced immunomodulatory TNBC. PATIENTS AND METHODS: This open-label, single-arm, phase II study enrolled patients with previously untreated, advanced, immunomodulatory TNBC (CD8 IHC staining ≥10%). Eligible patients received 20 mg of oral famitinib on days 1 to 28, 200 mg of i.v. camrelizumab on days 1 and 15, and i.v. nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 in 4-week cycles. The primary endpoint was objective response rate (ORR), as assessed by investigators per RECIST v1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), safety, and exploratory biomarkers. RESULTS: Forty-eight patients were enrolled and treated. Median follow-up was 17.0 months (range, 8.7-24.3). Confirmed ORR was 81.3% [95% confidence interval (CI), 70.2-92.3], with five complete and 34 partial responses. Median PFS was 13.6 months (95% CI, 8.4-18.8), and median DOR was 14.9 months [95% CI, not estimable (NE)-NE]. Median OS was not reached. No treatment-related deaths were reported. Among 30 patients with IHC, 13 (43.3%) were programmed death-ligand 1 (PD-L1)-negative, and PD-L1 was associated with favorable response. PKD1 and KAT6A somatic mutations were associated with therapy response. CONCLUSIONS: The triplet regimen was efficacious and well tolerated in previously untreated, advanced, immunomodulatory TNBC. The randomized controlled FUTURE-SUPER trial is under way to validate our findings. See related commentary by Salgado and Loi, p. 2728.

Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial.

BACKGROUND: Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. METHODS: We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. RESULTS: CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. CONCLUSION: This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.

Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.

Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Comprehensive metabolomics expands precision medicine for triple-negative breast cancer.

Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC.

Updatable privacy-preserving K -nearest neighbor query in location-based s-ervice.

The K -nearest neighbor ( K -NN) query is an important query in location-based service (LBS), which can query the nearest k points to a given point, and provide some convenient services such as interest recommendations. Hence the privacy protection issue of K -NN query has been a popular research area, protecting the information of queries and the queried results, especially in the information era. However, most of existing schemes fail to consider the privacy protection of location points already stored on servers. Or some schemes support no update of location points. In this paper, we present an updatable and privacy-preserving K -NN query scheme to address the above two issues. Concretely, our scheme utilizes the K D-tree ( K -Dimensional tree) to store the location points of data owners in location service provider and encrypts the points with a distributed double-trapdoor public-key cryptosystem. Then, based on the Ciphertext Comparison Protocol and Ciphertext Euclidean Distance Calculation Protocol, our scheme can protect the privacy of location and query contents. Experimental analyses show our proposal supports some new location points for a fixed location service provider. Moreover, the queried results show a high accuracy of more than 95%.

Estrogen receptor-low breast cancer: Biology chaos and treatment paradox.

Hormone receptor testing mainly serves the purpose of guiding treatment choices for breast cancer patients. Patients with estrogen receptor (ER)-positive breast cancers show significant response to endocrine therapy. However, the methods to define ER status and eligibility for treatment remain controversial. Despite recent guidelines considering staining ≥1% of tumor nuclei by immunohistology as ER-positive, it has raised concerns on the benefit of endocrine therapy for tumors with ER 1%-10% expression, termed "ER-low positive". This subgroup accounts for 3% to 9% of all patients and is likely to have unique molecular features, and therefore distinct therapeutic response to endocrine therapy compared with ER-high positive tumors. The latest guidelines did not provide detailed descriptions for those patients, resulting in inconsistent treatment strategies. Consequently, we aimed to resolve this dilemma comprehensively. This review discusses molecular traits and recent ER-low positive breast cancer innovations, highlighting molecular-targeted treatment rather than traditional unified endocrine therapy for future basic and clinical research.

Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response.

Tumors are not only aggregates of malignant cells but also well-organized complex ecosystems. The immunological components within tumors, termed the tumor immune microenvironment (TIME), have long been shown to be strongly related to tumor development, recurrence and metastasis. However, conventional studies that underestimate the potential value of the spatial architecture of the TIME are unable to completely elucidate its complexity. As innovative high-flux and high-dimensional technologies emerge, researchers can more feasibly and accurately detect and depict the spatial architecture of the TIME. These findings have improved our understanding of the complexity and role of the TIME in tumor biology. In this review, we first epitomized some representative emerging technologies in the study of the spatial architecture of the TIME and categorized the description methods used to characterize these structures. Then, we determined the functions of the spatial architecture of the TIME in tumor biology and the effects of the gradient of extracellular nonspecific chemicals (ENSCs) on the TIME. We also discussed the potential clinical value of our understanding of the spatial architectures of the TIME, as well as current limitations and future prospects in this novel field. This review will bring spatial architectures of the TIME, an emerging dimension of tumor ecosystem research, to the attention of more researchers and promote its application in tumor research and clinical practice.

Triple-negative breast cancer: new treatment strategies in the era of precision medicine.

Triple-negative breast cancer (TNBC) remains the most aggressive cluster of all breast cancers, which is due to its rapid progression, high probabilities of early recurrence, and distant metastasis resistant to standard treatment. Following the advances in cancer genomics and transcriptomics that can illustrate the comprehensive profiling of this heterogeneous disease, it is now possible to identify different subclasses of TNBC according to both intrinsic signals and extrinsic microenvironment, which have a huge influence on predicting response to established therapies and picking up novel therapeutic targets for each cluster. In this review, we summarize basic characteristics and critical subtyping systems of TNBC, and particularly discuss newly found prospective targets and relevant medications, which were proved promising in clinical trials, thus shedding light on the future development of precision treatment strategies.

Natural killer cells in cancer biology and therapy.

The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.

C-C motif chemokine 22 predicts postoperative prognosis and adjuvant chemotherapeutic benefits in patients with stage II/III gastric cancer.

Immune molecules, which have been found to be important in tumor microenvironment, seem prospective in tumor therapy, but they are still not effective enough to use in clinical practice. C-C motif chemokine 22 (CCL22) exists in various malignancies and correlates with migration of regulatory T cells, but its clinical significance in gastric cancer is still unclear. In this study, a combined data set of 466 patients with gastric cancer after surgical resection, comprised of a discovery (n = 319) and a validation data set (n = 147), was enrolled. CCL22 expression was assessed by immunohistochemical staining and we evaluated prognostic values of CCL22 staining and clinical outcomes with use of Kaplan-Meier curve and Multivariate Cox regression analysis. Positive CCL22 expression predicted adverse overall survival independent of traditional pathological grade. Multivariate analysis defined CCL22 and TNM stage as two independent prognostic factors for overall survival. Besides, in patients with TNM stage II/III disease, the rate of overall survival was higher among patients with CCL22-positive tumors who were treated with 5-fluorouracil based adjuvant chemotherapy than that among those who were not (P = 0.012, P < 0.001 and P < 0.001, in discovery, validation and combined data set). But for these with CCL22-negative tumors, whether to undergo adjuvant chemotherapy showed no statistical significance (P = 0.595, P = 0.085 and P = 0.252, respectively). To conclude, CCL22 was identified as an independent adverse prognostic immunobiomarker for patients with gastric cancer after surgery, which is associated with tumor-infiltrating immunocytes and could be incorporated into TNM staging system to redefine a high-risk subgroup who were more likely to benefit from 5-fluorouracil based adjuvant chemotherapy.