Specific Tumor Microenvironment Research Articles

Next-generation sequencing identified that RET variation associates with lymph node metastasis and the immune microenvironment in thyroid papillary carcinoma

BackgroundTo date, although most thyroid carcinoma (THCA) achieves an excellent prognosis, some patients experience a rapid progression episode, even with differentiated THCA. Nodal metastasis is an unfavorable predictor. Exploring the underlying mechanism may bring a deep insight into THCA.MethodsA total of 108 THCA from Chinese patients with next-generation sequencing (NGS) were recruited. It was used to explore the gene alteration spectrum of THCA and identify gene alterations related to nodal metastasis in papillary thyroid carcinoma (PTC). The Cancer Genome Atlas THCA cohort was further studied to elucidate the relationship between specific gene alterations and tumor microenvironment. A pathway enrichment analysis was used to explore the underlying mechanism.ResultsGene alteration was frequent in THCA. BRAF, RET, POLE, ATM, and BRCA1 were the five most common altered genes. RET variation was positively related to nodal metastasis in PTC. RET variation is associated with immune cell infiltration levels, including CD8 naïve, CD4 T and CD8 T cells, etc. Moreover, Step 3 and Step 4 of the cancer immunity cycle (CIC) were activated, whereas Step 6 was suppressed in PTC with RET variation. A pathway enrichment analysis showed that RET variation was associated with several immune-related pathways.ConclusionRET variation is positively related to nodal metastasis in Chinese PTC, and anti-tumor immune response may play a role in nodal metastasis triggered by RET variation.

A Copper/Ferrous‐Engineering Redox Homeostasis Disruptor for Cuproptosis/Ferroptosis Co‐Activated Nanocatalytic Therapy in Liver Cancer

AbstractCuproptosis and ferroptosis hold great promise for overcoming apoptotic resistance in liver cancer based on their unique metal‐driven cell death modalities. However, insufficient intracellular copper and iron concentration, complicated tumor microenvironment (TME), and unclear cross‐regulatory mechanisms between cuproptosis and ferroptosis, severely restrict the therapeutic performance. Herein, copper‐doped hollow Prussian blue (CHP) nanozymes are rationally designed for loading photosensitizer indocyanine green (ICG) and O2‐saturated perfluorohexane (PFH), denoted as O2‐PFH@CHPI nanoparticles, to induce cuproptosis and ferroptosis. In response to the specific TME, the CHP nanozymes can synergistically catalyze Fenton reactions and consume endogenous glutathione, leading to the accumulation of reactive oxygen species. Upon near‐infrared irradiation, the O2‐PFH@CHPI‐enabled photothermal effect can simultaneously accelerate catalytic reactions and trigger O2 release for photodynamic therapy to promote oxidative stress. Notably, cuproptosis can be effectively activated through Cu+‐mediated dihydrolipoamide S‐acetyltransferase aggregation and Fe–S cluster protein loss. Concurrently, the tilt of redox balance is favorable for lipid peroxidation and glutathione peroxidase 4 inactivation, resulting in an augmented ferroptosis effect. Mechanistically, oxidative stress‐boosted cuproptosis and ferroptosis jointly disrupt mitochondrial metabolism, which in turn exacerbates intracellular oxidative stress, thus realizing a mutually enhanced therapeutic effect. This work may provide new guidance for utilizing copper/ferrous‐engineering nanozymes for cuproptosis/ferroptosis synergetic therapy.

Role of SPRY4 in health and disease.

SPRY4 is a protein encoding gene that belongs to the Spry family. It inhibits the mitogen-activated protein kinase (MAPK) signaling pathway and plays a role in various biological functions under normal and pathological conditions. The SPRY4 protein has a specific structure and interacts with other molecules to regulate cellular behavior. It serves as a negative feedback inhibitor of the receptor protein tyrosine kinases (RTK) signaling pathway and interferes with cell proliferation and migration. SPRY4 also influences inflammation, oxidative stress, and cell apoptosis. In different types of tumors, SPRY4 can act as a tumor suppressor or an oncogene. Its dysregulation is associated with the development and progression of various cancers, including colorectal cancer, glioblastoma, hepatocellular carcinoma, perihilar cholangiocarcinoma, gastric cancer, breast cancer, and lung cancer. SPRY4 is also involved in organ development and is associated with ischemic diseases. Further research is ongoing to understand the expression and function of SPRY4 in specific tumor microenvironments and its potential as a therapeutic target.

Integrating iron metabolism-related gene signature to evaluate prognosis and immune infiltration in nasopharyngeal carcinoma

BackgroundDysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC).MethodsMultiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored.ResultsA novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P < 0.0001). The prognostic model’s accuracy was additionally confirmed by employing time-dependent Receiver Operating Characteristic (ROC) curves and conducting Decision Curve Analysis (DCA). High-risk patients were found to correlate with advanced clinical stages, specific tumor microenvironment subtypes, and distinct morphologies. ESTIMATE analysis demonstrated a significant inverse relationship between increased immune, stromal, and ESTIMATE scores and lowered risk score. Immune analysis indicated a negative correlation between high-risk score and the abundance of most tumor-infiltrating immune cells, including dendritic cells, CD8+ T cells, CD4+ T cells, and B cells. This correlation extended to immune checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, and BTLA. The protein expression patterns of selected genes in clinical NPC samples were validated through immunohistochemistry.ConclusionThis study presents a prognostic model utilizing IMRGs in NPC, which could assist in assessing patient prognosis and provide insights into new therapeutic targets for NPC.

Abstract 3931: Breast cancer genomic architecture contributes to immune escape across metastasis

Abstract Clinically, breast tumors are stratified based on the expression of three receptors - estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Breast cancer is a highly heterogeneous disease, and a more detailed understanding of its genomic drivers, mechanisms of immune evasion, and evolution may inform more effective and personalized treatment. Previously, we established a genome-driven breast cancer classification scheme that defines 11 integrative subgroups (ICs) of disease with distinct copy number aberrations (CNAs), transcriptional profiles, and clinical outcomes. Specifically, we identify four subgroups of ER+ disease (IC1, IC2, IC6, IC9) with a persistent risk of lethal distant relapse up to two decades after diagnosis, each with focal copy number drivers and two distinct subgroups of triple-negative disease (Curtis et al. Nature 2012; Rueda et al. Nature 2019). These findings nominate new therapeutic strategies, however, it is not known how mutational processes and genomic architecture differ across the ICs to sculpt the development and evolution of disease, nor how their microenvironments differ. To interrogate the genomic and immune landscape of breast cancer throughout the disease continuum, we established a meta-cohort of 2,873 breast tumors spanning pre-invasive (ductal carcinoma in situ), primary invasive, and metastatic breast cancer, including 1,865 with whole-genome sequencing, 1,738 with whole-transcriptome sequencing, and 730 with both modalities. We developed a fully containerized bioinformatic workflow to interrogate copy number alterations, complex classes of structural variation, and neoantigens. Analysis of this large clinically curated compendium identifies highly concordant mutational signatures and higher order genomic features in high-risk ER+ (IC1,2,6,9) and HER2+ (IC5) tumors, including distinct patterns of structural variation. In contrast, triple-negative tumors (predominantly IC10) were characterized by global genomic instability and tandem duplications, whilst a third group is largely genomically stable. These distinct genomic architectures were associated with specific tumor microenvironments. As expected, triple-negative tumors were immune-enriched. In contrast high-risk ER+ and HER2+ tumors demonstrated immune-depleted profiles, as compared to typical risk ER+ tumors. These microenvironment classifications were maintained from primary tumors to metastatic lesions, except triple-negative tumors that exhibited increased immune depletion during metastasis. Taken together, our data demonstrate that complex structural alterations established early in breast cancer contribute to immune evasion, and persist throughout the life history of the tumor through metastasis. Citation Format: Lise Mangiante, Kathleen Houlahan, Cristina Sotomayor Vivas, Alvina Adimoelja, Seongyeol Park, Aziz Khan, Sophie Pribus, Zhicheng Ma, Jennifer Caswell-Jin, Christina Curtis. Breast cancer genomic architecture contributes to immune escape across metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3931.

Abstract 1017: Characterizing immune cell infiltration in colorectal cancer tumor microenvironment among Native Hawaiians

Abstract Background Colorectal cancer (CRC) is recognized as a heterogeneous disease, ranking third in new cancer diagnoses and second in cancer-related deaths globally and nationally. CRC incidence is higher in the state of Hawaii compared to the U.S. overall. This study focuses on profiling immune cell infiltration in Native Hawaiian(NH)-specific CRC tumor microenvironments. Identifying the race-specific tumor infiltrating microenvironment may uncover potential mechanisms for CRC development in the NH population. Methods Deidentified, archival formalin-fixed paraffin-embedded tumor samples from Native Hawaiian patients diagnosed with primary CRC between 1990 and 2006 were obtained from the Hawaii Tumor Registry. RNA was extracted from tumor and adjacent normal tissues. RNA-seq data from Caucasian American (CA) CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Differentially expressed genes for each cohort were identified via DESeq2 with Benjamini-Hochberg multiple testing q-value&amp;lt;0.05 and a cutoff of 2-fold change. From the gene expression profiles, we applied the ESTIMATE algorithm to calculate the overall immune cell infiltration score for each sample. Based on a deconvolution algorithm, known as CIBERSORT to estimate the abundance of 22 immune cell types, we profiled the tumor-infiltrating immune cells present in each cohort’s paired samples, respectively. To improve the accuracy, p-value and root mean squared error were counted for each sample. Data with p&amp;lt;0.05 were filtered and selected for the next analysis. The fraction of immune cell subpopulations was evaluated and compared between paired tumor and adjacent normal tissues in NH and CA cohorts. Results In the NH cohort, we found the overall immune cell infiltration score was significantly lower in cancer tissues than the adjacent normal tissues (p&amp;lt;0.05), and there were significantly higher fractions of activated dendritic cells, resting natural killer (NK), and follicular helper T cells in tumor tissues compared to adjacent non-tumor tissues (p&amp;lt;0.05). Furthermore, the fractions of activated NK cells and plasma cells were significantly lower in tumor tissues than in adjacent non-tumor tissues in NH (p&amp;lt;0.05). Resting NK cells are upregulated in both the NH and the CA cohorts, while plasma cells are the only immune cell type downregulated in either cohort. In the NH cohort, activated dendritic cells and follicular helper T cells are exclusively upregulated, while activated NK cells are downregulated relative to the CA cohort. Conclusion This study demonstrates that the NH cohort displays distinctive immunological variances between tumor and adjacent non-tumor tissues which distinguishes them from the CA cohort. This emphasizes the significance of acknowledging population-specific genetic variations which may help understand race specific difference in CRC. Citation Format: Yuanyuan Fu, Gino Quintal, Masaki Nasu, Mayumi Jijiwa, Sudhir K. Rai, Isam Mohd-Ibrahim, Yu Chen, Hua Yang, Zhanwei Wang, Christina Wai, Owen Chan, Brenda Y. Hernandez, Youping Deng. Characterizing immune cell infiltration in colorectal cancer tumor microenvironment among Native Hawaiians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1017.

Abstract 6957: Extrachromosomal FGFR2 is delivered in extracellular vesicles in two models of cancer of unknown primary

Abstract The extracellular vesicle (EV) route is essential for cell-to-cell communication. Cancer cells release EVs in the extracellular space, where they can interact with recipient cells inducing regulation of gene expression, activation of specific signaling pathways and tumor microenvironment remodeling. We investigated the EVs released by two cell lines of cancer of unknown primary site (CUP) that we established from patient’s tumor cells, namely CUP#55 and CUP#96, as described in https://www.medrxiv.org/content/10.1101/2023.03.12.23287041v1). CUP comprises 3-5% of new cancer cases and presents with metastases of unknown or uncertain origin and no apparent primary tumor. Our CUP cell lines are both characterized by FGFR2 gene amplification. It has been recognized that tumors use circular extrachromosomal DNA (ecDNA) as a way to increase oncogenic amplification. We hypothesized that FGFR2 amplification in CUP cell lines could be associated with ecDNA generation and that this ecDNA could be loaded as cargo inside EVs. FGFR2 copy number was quantified using a probe-based droplet digital PCR assay then we identified the different nature of FGFR2 amplification in the two models using FGFR2 FISH assay: CUP#55 presented a chromosomal homogeneously staining region while CUP#96 displayed double minute chromosomes. FGFR2 DNA was detectable in the cytoplasm fraction, therefore we isolated extracellular vesicles from culture medium using an ultracentrifugation-based protocol and confirmed the presence of the entire length of FGFR2 gene inside small and large vesicles. Since ecDNA contributes to cancer genome remodeling also forming chimeric circles, we confirmed the circular nature of a fraction of FGFR2 ecDNA using the Plasmid-Safe ATP-dependent DNAse test. Finally, we tested the oncogene delivery capability of CUP EVs by administering CUP#96 and CUP#55 small and large vesicles to recipient cell lines. We observed an increase of FGFR2 DNA at 24 hours upon EV treatments, and its functional transcription in FGFR2 mRNA after 48 hours. In conclusion, we identified a model of oncogene amplification and delivery in two cell lines of cancer of unknown primary, which could explain the high metastatic potential of this cancer type. (The research leading to these results has received funding from AIRC under IG 2021 - ID. 25789 project - P.I. Ferracin Manuela) Citation Format: Irene Salamon, Gianluca Storci, Beatrice Fontana, Salvatore Serravalle, Giulia Gallerani, Roberta Roncarati, Spartaco Santi, Massimiliano Bonafè, Manuela Ferracin. Extrachromosomal FGFR2 is delivered in extracellular vesicles in two models of cancer of unknown primary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6957.

Abstract 3906: Ex vivo breast tumors for understanding the patient specific tumor microenvironment remodeling and drug responses

Abstract Breast cancer is a heterogeneous disease driven by cell-intrinsic and cell-extrinsic signaling cues. Many of these cues derive from the tumor microenvironment (TME), which is composed of adipocytes, vasculature, stem cells, immune cells, and the extracellular matrix (ECM). Through these diverse components, the TME modulates cellular proliferation, survival, and ultimately response to therapy. Despite this high-level understanding of tumor-TME crosstalk, no existing pre-clinical models accurately capture the TME in vitro. We overcame that hurdle by developing a method to maintain healthy human breast tissue (HBT) alive ex vivo for at least 8 weeks. By culturing breast cancer cells in that HBT, we created ex vivo breast tumors (EVBTs) that retained patient-specific features relevant to breast cancer including menopause status, obesity status, and response to therapy. Using these EVBTs, we demonstrate breast cancer subtype-specific alterations in lipid accumulation, ECM remodeling, and cytokine profiles. RNA sequencing showed that breast cancer cell line signatures were retained in the EVBTs system at 1 week and 2 weeks in vitro. We demonstrated donor-specific transcriptional changes to the core matrisome gene set. Finally, we demonstrate that our EVBTs retained patient-specific heterogeneity in response to standard of care endocrine therapy and neoadjuvant chemotherapies. Our novel tumor model allows for 1) real-time examination of breast cancer interactions with HBT and the TME and 2) the isolation of breast cancer-specific factors vs. patient-specific factors in the development and progression of breast cancer. Citation Format: Elizabeth Martin, Megan Benz, Katie Hebert, Ethan Byrne, Frank Lau. Ex vivo breast tumors for understanding the patient specific tumor microenvironment remodeling and drug responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3906.

Abstract 1621: Integrated analysis of genetic, transcriptional and TME evolution of ccRCC: TRACERx Renal

Abstract Background: Genetic evolution of clear cell renal cell carcinoma (ccRCC) follows distinct trajectories, with varying levels of intratumor heterogeneity (ITH) and chromosomal complexity (WGII). While these patterns associate with clinical outcomes, it remains unknown whether they fully reconcile tumor behavior and how genetic and transcriptional features co-evolve in relation to the tumor microenvironment (TME). Methods: To analyze the patterns of transcriptional and TME heterogeneity, we performed bulk whole-transcriptome sequencing on 244 samples, including 22 metastatic and 12 tumor-adjacent normal samples, from 79 ccRCC patients recruited to the TRACERx Renal study. We integrated transcriptional data with previously published genetic, phylogenetic, spatial and clinical information. Results: Transcriptional distances between paired samples from the same primary tumor mirrored but were not fully determined by genetic distance (p-value &amp;lt; 0.001); and increased from primary-primary to primary-metastasis and primary-normal pairs. Within primary-metastasis pairs, metastasis-seeding primary tumor regions were transcriptionally closest to their matched metastasis (p-value &amp;lt; 0.001), suggesting that an important fraction of metastatic transcriptional traits were acquired in the primary tumor. Regarding the tumor clonal structure, transcriptional evolution followed a conserved path through increasing cell proliferation and oxidative phosphorylation and downregulating DNA repair from earlier to later clones. Further, within tumors with increasing WGII we observed upregulation and downregulation of repressors and downstream effectors, respectively, of the canonical cGAS-STING pathway. Combining the presence of this transcriptional pattern with WGII predicted shorter PFS in TRACERx Renal (p-value &amp;lt; 0.001) and in TCGA-KIRC (p-value &amp;lt; 0.001). Clonal evolution was also linked to changes in TME, with each of the previously defined genetic evolutionary trajectories associated to a specific TME (p-value &amp;lt; 0.001). For example, ccRCCs on a PBRM1-SETD2 trajectory demonstrated increased infiltration of cytotoxic immune cells. TME ITH was pervasive and associated with shorter PFS (p-value = 0.03). A recurrent trend from earlier to later clones was progressive T cell depletion (p-value &amp;lt; 0.001). The evolution of the TCR repertoire mirrored the tumor clonal structure (p-value = 0.002), suggesting the thus far elusive antigenic source in ccRCC is heritable. Accordingly, the TCR repertoire in metastasis-seeding primary tumor regions resembled the closest the TCR repertoire of matched metastasis (p-value = 0.06). Conclusion: Integrated analysis of genetic and transcriptional data in TRACERx Renal showed i) transcriptional and TME ITH not fully recapitulated by genetic ITH, ii) conserved paths of transcriptional and TME evolution and iii) a heritable nature of part of the ccRCC antigen source. Citation Format: Ángel Fernández Sanromán, Lewis Au, Benjy Jek Yang Tan, Charlotte Spencer, Anne-Laure Catin, Irene Lobon, Husayn Pallikonda, Kevin Litchfield, Fiona Byrne, James Larkin, Annika Fendler, Samra Turajlic. Integrated analysis of genetic, transcriptional and TME evolution of ccRCC: TRACERx Renal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1621.

Analyzing the impact of metabolism on immune cells in tumor microenvironment to promote the development of immunotherapy.

Tumor metabolism and tumor immunity are inextricably linked. Targeting the metabolism of tumors is a point worth studying in tumor immunotherapy. Recently, the influence of the metabolism of tumors and immune cells on the occurrence, proliferation, metastasis, and prognosis of tumors has attracted more attention. Tumor tissue forms a specific tumor microenvironment (TME). In addition to tumor cells, there are also immune cells, stromal cells, and other cells in TME. To adapt to the environment, tumor cells go through the metabolism reprogramming of various substances. The metabolism reprogramming of tumor cells may further affect the formation of the tumor microenvironment and the function of a variety of cells, especially immune cells, eventually promoting tumor development. Therefore, it is necessary to study the metabolism of tumor cells and its effects on immune cells to guide tumor immunotherapy. Inhibiting tumor metabolism may restore immune balance and promote the immune response in tumors. This article will describe glucose metabolism, lipid metabolism, amino acid metabolism, and immune cells in tumors. Besides, the impact of metabolism on the immune cells in TME is also discussed for analyzing and exploring tumor immunotherapy.

Evaluation of Interleukin-17 A Levels in Patients with Breast Carcinoma

Breast cancer is a highly common form of cancer that impacts a considerable proportion of women on a global scale. Interleukin 17A (IL-17A) is a cytokine that has both anti-tumor and pro-tumor effects, which can vary depending on the specific tumor microenvironment. The aim of this study was to determine whether IL-17A can be used as a biomarker for diagnosis of breast cancer. Therefore, we compared concentrations of serum IL-17A in patients suffering from breast carcinoma and normal control women by an enzyme-linked immunosorbent assay (ELISA). This study included 86 women, 44 patients that were diagnosed with breast carcinoma, and 42 normal control women. Serum IL-17A levels in both case and control groups were measured by sandwich ELISA kits. The IL-17A serum level was significantly higher among patients with breast carcinoma than in the control group (p&lt;0.001). The serum IL-17A concentration was significantly higher in estrogen receptor-positive cases than in estrogen receptor-negative cases (p=0.033). The highest levels of IL-17A were detected in patients with stage 2 breast carcinoma rather than stage 3 with no significant correlation. There was no correlation between IL-17A level and tumor size, lymph node invasion, or metastasis in patients with breast cancer. In conclusion, a high level of IL-17A in breast carcinoma patients compared to the control group was detected in our study. It indicates that IL-17A could be a promising biomarker for diagnosis of breast cancer and may play a role in tumor development. High levels of IL-17A were not a predictor of poor prognosis in breast cancer patients as it was not related to tumor size, lymph node invasion, or metastasis.

Cellular interactions in tumor microenvironment during breast cancer progression: new frontiers and implications for novel therapeutics.

The breast cancer tumor microenvironment (TME) is dynamic, with various immune and non-immune cells interacting to regulate tumor progression and anti-tumor immunity. It is now evident that the cells within the TME significantly contribute to breast cancer progression and resistance to various conventional and newly developed anti-tumor therapies. Both immune and non-immune cells in the TME play critical roles in tumor onset, uncontrolled proliferation, metastasis, immune evasion, and resistance to anti-tumor therapies. Consequently, molecular and cellular components of breast TME have emerged as promising therapeutic targets for developing novel treatments. The breast TME primarily comprises cancer cells, stromal cells, vasculature, and infiltrating immune cells. Currently, numerous clinical trials targeting specific TME components of breast cancer are underway. However, the complexity of the TME and its impact on the evasion of anti-tumor immunity necessitate further research to develop novel and improved breast cancer therapies. The multifaceted nature of breast TME cells arises from their phenotypic and functional plasticity, which endows them with both pro and anti-tumor roles during tumor progression. In this review, we discuss current understanding and recent advances in the pro and anti-tumoral functions of TME cells and their implications for developing safe and effective therapies to control breast cancer progress.

CD200/CD200R: Bidirectional Role in Cancer Progression and Immunotherapy.

As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.

Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer.

Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored host-microbiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1-CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga. Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella, contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets.NEW & NOTEWORTHY This study determined the following: 1) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME.

Novel biomarker genes for the prediction of post-hepatectomy survival of patients with NAFLD-related hepatocellular carcinoma

BackgroundThe incidence and prevalence of nonalcoholic fatty liver disease related hepatocellular carcinoma (NAFLD-HCC) are rapidly increasing worldwide. This study aimed to identify biomarker genes for prognostic prediction model of NAFLD-HCC hepatectomy by integrating text-mining, clinical follow-up information, transcriptomic data and experimental validation.MethodsThe tumor and adjacent normal liver samples collected from 13 NAFLD-HCC and 12 HBV-HCC patients were sequenced using RNA-Seq. A novel text-mining strategy, explainable gene ontology fingerprint approach, was utilized to screen NAFLD-HCC featured gene sets and cell types, and the results were validated through a series of lab experiments. A risk score calculated by the multivariate Cox regression model using discovered key genes was established and evaluated based on 47 patients’ follow-up information.ResultsDifferentially expressed genes associated with NAFLD-HCC specific tumor microenvironment were screened, of which FABP4 and VWF were featured by previous reports. A risk prediction model consisting of FABP4, VWF, gender and TNM stage were then established based on 47 samples. The model showed that overall survival in the high-risk score group was lower compared with that in the low-risk score group (p = 0.0095).ConclusionsThis study provided the landscape of NAFLD-HCC transcriptome, and elucidated that our model could predict hepatectomy prognosis with high accuracy.

PEG-modified carbon-based nanoparticles as tumor-targeted drug delivery system reducing doxorubicin-induced cardiotoxicity

Herein, a doxorubicin-loaded carbon-based drug delivery system, denoted as PC-DOX, composed of pH-responsive imine bond was developed for the tumor-targeted treatment. PC-DOX with a uniform particle size around 180 nm was synthesized by coating of as-synthesized hollow carbon-based nanoparticles (NPs) with dialdehyde PEG, which was used as carrier to attach DOX covalently through dynamic covalent bond. The unique structure endowed the advantages of specific tumor targeting and tumor microenvironment (TME) specific drug delivery capacity with PC-DOX. For the one hand, the tumor targeting caused by the enhanced permeability and retention (EPR) effect could significantly improve the tumor cellular uptake. For the other hand, the pH-responsiveness could realize the effective DOX accumulation in tumor tissues, avoiding the unwanted side effect to the normal tissues. As a result, PC-DOX with high DOX loading capacity (70.12%) and excellent biocompatibility, concurrently, presented a significant anti-tumor effect at a low mass concentration (DOX equivalent dose: 20 μg/mL). Another attractive characteristic of PC-DOX was the remarkable protective effect towards DOX-induced cardiotoxicity, which could be clearly observed from in vitro cellular, and animal assays. Compared with free DOX, the cardiomyocyte viability increased by average 30.58%, and the heart function was also significantly improved. This novel drug delivery nanoplatform provides a new method for the future clinical application of DOX in the cancer’s therapeutics.

Comprehensive analysis of HOXC8 associated with tumor microenvironment characteristics in colorectal cancer

BackgroundAccumulating evidence have highlighted the essential roles of HOX genes in embryonic development and carcinogenesis. As a member of the HOX gene family, the abnormal expression of HOXC8 gene is associated with the progression and metastasis of various tumors. However, potential roles of HOXC8 in colorectal cancer (CRC) prognosis and tumor microenvironment (TME) remodeling remain unclear. MethodsWe conducted an integrated analysis of clinical and molecular characteristics, relevant oncogenic and immune regulation roles and drug sensitivity features of HOXC8 in CRC. ResultsHOXC8 expression was markedly high expressed in CRC samples compared to normal samples, and the upregulated expression of HOXC8 was associated with poor prognosis. High HOXC8 expression was significantly associated with invasion-related pathways especially epithelial-mesenchymal transition (EMT). In vitro experiments showed significantly up-regulated HOXC8 expression in some CRC cell lines and its promoting effect on EMT and cell proliferation. TME categorization through transcriptomic analysis of CRC patients with high HOXC8 expression identified two different TME subtypes known as immune-enriched with fibrotic subtype and immune-depleted subtype. Patients with immune-enriched, fibrotic subtype exhibited significantly longer progression-free survival (PFS), upregulated PD-L1 and CTLA4 expression and higher TMB than those with the immune-depleted subtype. ConclusionsHOXC8 overexpression was associated with poor prognosis and specific TME subtypes in CRC. This study provided valuable resource for further exploring the potential mechanisms and therapeutic targets of HOX genes in CRC.

CD22 is a potential target of CAR-NK cell therapy for esophageal squamous cell carcinoma

BackgroundChimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic malignancies, few successes have been obtained in solid tumors including esophageal squamous cell carcinoma (ESCC). The major reasons are lack of specific cell surface antigens and complex tumor microenvironment. Here we identify CD22, a well-known tumor surface marker in hematologic malignancies, is expressed in ESCC, possibly serving as a potential target of CAR-NK cell therapy.MethodsThe expression of 13 tumor cell surface antigens used clinically was analyzed in patients from The Cancer Genome Atlas (TCGA) database. Also, mRNA expression were detected in 2 ESCC cell lines and 2 patients samples by qCPR. Then according to Venn diagram, CD22 was selected for further investigation. Following this, the expression of CD22 by immunofluorescence (IF) in ESCC cell lines and by immunohistochemistry (IHC) in 87 cases of human ESCC samples was detected respectively. On the basis of H-score results, the correlation between CD22 expression and clinical parameters was analyzed. As a proof, the efficacy of CD22-targeted CAR-NK cells against ESCC cell lines was performed by a real-time cell analyzer (RTCA) platform.ResultsKYSE-140 and KYSE-150 cell lines displayed surface expression of CD22. IHC showed an 80.46% (70/87) positive rate in ESCC patient samples. Among these, cell membranous expression of CD22 was observed in 27.59% (24/87) patient samples. Through chi-square test, expression of CD22 in ESCC was associated with lymph node metastasis while it was no related to the depth of tumor invasion and clinical stage. Engineered CD22-targeted CAR-NK cells exhibited inhibitory growth capability against ESCC cell lines (p < 0.0001).ConclusionsCD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.

The mycosis fungoides cutaneous microenvironment shapes dysfunctional cell trafficking, antitumor immunity, matrix interactions, and angiogenesis.

Malignant T lymphocyte proliferation in mycosis fungoides (MF) is largely restricted to the skin, implying that malignant cells are dependent on their specific cutaneous tumor microenvironment (TME), including interactions with non-malignant immune and stromal cells, cytokines, and other immunomodulatory factors. To explore these interactions, we performed a comprehensive transcriptome analysis of the TME in advanced-stage MF skin tumors by single-cell RNA sequencing. Our analysis identified cell-type compositions, cellular functions, and cell-to-cell interactions in the MF TME that were distinct from those from healthy skin and benign dermatoses. While patterns of gene expression were common among patient samples, high transcriptional diversity was also observed in immune and stromal cells, with dynamic interactions and crosstalk between these cells and malignant T lymphocytes. This heterogeneity mapped to processes such as cell trafficking, matrix interactions, angiogenesis, immune functions, and metabolism that affect cancer cell growth, migration, and invasion, as well as antitumor immunity. By comprehensively characterizing the transcriptomes of immune and stromal cells within the cutaneous microenvironment of individual MF tumors, we have identified patterns of dysfunction common to all tumors that represent a resource for identifying candidates with therapeutic potential as well as patient-specific heterogeneity that has important implications for personalized disease management.

The specific viral composition in triple-negative breast cancer tissue shapes the specific tumor microenvironment characterized on pathological images

Numerous studies have shown that different subtypes of breast cancer (BC) have significant differences in terms of the tumor microbiome, host gene expression, and histopathological image, whereas the biological links between these cancer-associated indicators are still unknown. Here, we performed a comprehensive analysis with 610 patients of the four subtypes of BC with matched tissue microbiota, host transcriptome, and histopathological image samples. Correlation analysis showed that the composition of intratumoral viruses shaped the tumor microenvironment (TME) of patients with BC, and the TME was further reflected in the histopathological images. Of the four subtypes, patients with triple-negative breast cancer (TNBC) had unique intratumoral viral community composition, non-cancer cell infiltration in the TME, and histopathological image characteristics. Furthermore, we detected multiple virus-cell-image association axes in TNBC, in which tumor-associated macrophages (TAMs) have clinical prognostic implication. This study provides a comprehensive map of the associations between the intratumoral virome, TME, and histopathological image of TNBC, as well as insights into disease prognosis that can be crucial for precise therapeutic intervention strategies.