Immunological Landscape Research Articles

Chromatin regulators-related lncRNA signature predicting the prognosis of kidney renal clear cell carcinoma and its relationship with immune microenvironment: A study based on bioinformatics and experimental validation.

Background: Kidney Renal Clear cell carcinoma (KIRC) is a major concern in the urinary system. A lot of researches were focused on Chromatin Regulators (CRs) in tumors. In this study, CRs-related lncRNAs (CRlncRNAs) were investigated for their potential impact on the prognosis of KIRC and the immune microenvironment. Methods: The TCGA database was used to obtain transcriptome and related clinical information. CRs were obtained from previous studies, whereas CRlncRNAs were obtained by differential and correlation analysis. We screened the lncRNAs for the signature construction using regression analysis and LASSO regression analysis. The effectiveness of the signature was evaluated using the Kaplan-Meier (K-M) curve and Receiver Operating Characteristic curve (ROC). Additionally, we examined the associations between the signature and Tumor Microenvironment (TME), and the efficacy of drug therapy. Finally, we further verified whether these lncRNAs could affect the biological function of KIRC cells by functional experiments such as CCK8 and transwell assay. Results: A signature consisting of 8 CRlncRNAs was constructed to predict the prognosis of KIRC. Quantitative Real-Time PCR verified the expression of 8 lncRNAs at the cell line and tissue level. The signature was found to be an independent prognostic indicator for KIRC in regression analysis. This signature was found to predict Overall Survival (OS) better for patients in the subgroups of age, gender, grade, stage, M, N0, and T. Furthermore, a significant correlation was found between riskScore and immune cell infiltration and immune checkpoint. Finally, we discovered several drugs with different IC50 values in different risk groups using drug sensitivity analysis. And functional experiments showed that Z97200.1 could affect the proliferation, migration and invasion of KIRC cells. Conclusion: Overall, the signature comprised of these 8 lncRNAs were reliable prognostic biomarkers for KIRC. Moreover, the signature had significant potential for assessing the immunological landscape of tumors and providing individualized treatment.

Understanding the immunological landscape of England during SARS-CoV2 Omicron variant wave.

Understanding the scale of the threat posed by SARS-CoV2 B.1.1.529, or Omicron, variant formed a key problem in public health in the early part of 2022. Early evidence indicated that the variant was more transmissible and less severe than previous variants. As the virus was expected to spread quickly through the population of England, it was important that some understanding of the immunological landscape of the country was developed. This paper attempts to estimate the number of people with good immunity to the Omicron variant, defined as either recent infection with two doses of vaccine, or two doses of vaccine with a recent booster dose. To achieve this, we use a process of iterative proportional fitting to estimate the cell values of a contingency table, using national immunisation records and real-time model infection estimates as marginal values. Our results indicate that, despite the increased risk of immune evasion with the Omicron variant, a high proportion of England’s population had good immunity to the virus, particularly in older age groups. However, low rates of immunity in younger populations may allow endemic infection to persist for some time.

TDO2+ myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma.

Characterization of the dynamic change in the immunological landscape during malignant transformation from precancerous lesions to cancerous lesions in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here, we performed single-cell RNA-Seq (scRNA-Seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 samples of precancerous oral leukoplakia, and 8 adjacent normal samples. We found that tumor-infiltrating CD4+ and CD8+ T cells were functionally inhibited by immunosuppressive ligands expressed on various types of myeloid cells or neutrophils in the process of oral carcinogenesis. Notably, we identified a subset of myofibroblasts that exclusively expressed tryptophan 2,3-dioxygenase (TDO2). These TDO2+ myofibroblasts were located distally from tumor nests, and both CD4+ and CD8+ T cells were enriched around them. Functional experiments revealed that TDO2+ myofibroblasts were more likely to possess the ability for chemotaxis toward T cells but induced the transformation of CD4+ T cells into Tregs and caused CD8+ T cell dysfunction. We further showed that use of the TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored the T cell antitumor response, and prevented the progression of OSCC malignant transformation in murine models. Our study reveals a multistep transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.

Durable Responses to Anti-PD1 and Anti-CTLA4 in a Preclinical Model of Melanoma Displaying Key Immunotherapy Response Biomarkers.

Simple SummaryImmunotherapy has improved the outcomes of patients with advanced melanoma, although many patients will progress while on treatment. Preclinical animal models provide valuable insights into immunotherapy response or resistance and can be used to test novel treatment combinations. The development of animal cancer models rarely involves the systematic analysis and inclusion of predictive biomarkers of immunotherapy response. This study describes a biomarker-driven workflow to generate a transplantable mouse melanoma model responsive to anti-PD1 and anti-CTLA4 immunotherapy. This model recapitulates human immunotherapy-responding tumor phenotypes and provides unique insights into the discrete mechanisms underlying the durability of response to immune checkpoint inhibitors.Immunotherapy has transformed the management of patients with advanced melanoma, with five-year overall survival rates reaching 52% for combination immunotherapies blocking the cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and programmed cell death-1 (PD1) immune axes. Yet, our understanding of local and systemic determinants of immunotherapy response and resistance is restrained by the paucity of preclinical models, particularly those for anti-PD1 monotherapy. We have therefore generated a novel murine model of melanoma by integrating key immunotherapy response biomarkers into the model development workflow. The resulting YUMM3.3UVRc34 (BrafV600E; Cdkn2a–/–) model demonstrated high mutation burden and response to interferon (IFN)γ, including induced expression of antigen-presenting molecule MHC-I and the principal PD1 ligand PD-L1, consistent with phenotypes of human melanoma biopsies from patients subsequently responding to anti-PD1 monotherapy. Syngeneic immunosufficient mice bearing YUMM3.3UVRc34 tumors demonstrated durable responses to anti-PD1, anti-CTLA4, or combined treatment. Immunotherapy responses were associated with early on-treatment changes in the tumor microenvironment and circulating T-cell subsets, and systemic immunological memory underlying protection from tumor recurrence. Local and systemic immunological landscapes associated with immunotherapy response in the YUMM3.3UVRc34 melanoma model recapitulate immunotherapy responses observed in melanoma patients and identify discrete immunological mechanisms underlying the durability of responses to anti-PD1 and anti-CTLA4 treatments.

The Immune Contexture of Liposarcoma and Its Clinical Implications.

Simple SummaryLiposarcomas (LPS) are malignancies arising from adipose tissue. Based on the histological appearance, five subtypes are distinguished: well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. Immune cells can infiltrate the tumor microenvironment (TME) of LPS and can either promote an efficient antitumor immune response or mediate immunosuppression paving the way for immune evasion of the tumor. The LPS subtypes display different TME characteristics and vary in regard to immune cell infiltration, ranging from the generally lowly infiltrated MLPS to the highly infiltrated DDLPS where immunological determinants predict response to novel antibody-based immunotherapy. Thus, immune cells in the TME can significantly affect response to therapy, disease progression, and patient survival. This review aims to decipher the immune contexture of LPS as well as its clinical association and highlights differences between the LPS subtypes that may have implications for the design of novel treatment strategies.Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS.

African Ancestry-Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent.

Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483.

Protein Profiling of Breast Carcinomas Reveals Expression of Immune-Suppressive Factors and Signatures Relevant for Patient Outcome.

Simple SummaryBreast cancer treatment has improved substantially over the last decade. Still, the failure of treatment and therapy resistance are urgent problems. Here, we assessed cellular signaling within primary cancer tissue to evaluate the possibility of developing strategies that lead to better patient stratification and the development of personalized treatment options. By employing DigiWest technology, the expression and activation of the regulators of key signaling pathways in breast cancer tissue were monitored. A positive correlation between immune cell infiltration and event-free survival was detected. PPARγ activation showed a negative correlation with immune cell infiltration, suggesting a novel immune evasion mechanism.In cancer, the complex interplay between tumor cells and the tumor microenvironment results in the modulation of signaling processes. By assessing the expression of a multitude of proteins and protein variants in cancer tissue, wide-ranging information on signaling pathway activation and the status of the immunological landscape is obtainable and may provide viable information on the treatment response. Archived breast cancer tissues from a cohort of 84 patients (no adjuvant therapy) were analyzed by high-throughput Western blotting, and the expression of 150 proteins covering central cancer pathways and immune cell markers was examined. By assessing CD8α, CD11c, CD16 and CD68 expression, immune cell infiltration was determined and revealed a strong correlation between event-free patient survival and the infiltration of immune cells. The presence of tumor-infiltrating lymphocytes was linked to the pronounced activation of the Jak/Stat signaling pathway and apoptotic processes. The elevated phosphorylation of PPARγ (pS112) in non-immune-infiltrated tumors suggests a novel immune evasion mechanism in breast cancer characterized by increased PPARγ phosphorylation. Multiplexed immune cell marker assessment and the protein profiling of tumor tissue provide functional signaling data facilitating breast cancer patient stratification.

Unveiling the molecular features, relevant immune and clinical characteristics of SIGLEC15 in thyroid cancer.

The groundbreaking research work about SIGLEC15 has raised it as a potential promising target in cancer immunotherapy. Unfortunately, the role of SIGLEC15 in thyroid carcinoma (THCA) remains obscure. Public and home multi-omics data were collected to investigate the role of SIGLEC15 in THCA in our study. SIGLEC15 was upregulated in THCA tumor tissue compared to nontumor tissue in both mRNA and protein levels; gene set enrichment analysis (GSEA) results showed that high SIGLEC15 mRNA expression was positively correlated to many immune pathways. Results of the examination of immunological landscape characteristics displayed high SIGLEC15 mRNA expression that mainly positively correlated with a large number of cancer immunity immunomodulators and pathways. In addition, upregulation of SIGLEC15 was positively correlated with an enhanced immune score, stromal score, and estimate score. However, higher SIGLEC15 mRNA also met high immune exhausted status. The majority of CpG methylation sites negatively correlated with SIGLEC15 mRNA expression. Analysis of clinical characteristics supported increased SIGLEC15 expression that was positively correlated with more extrathyroid extension and lymph node metastasis. We observed different single nucleotide variant (SNV) and copy number variation (CNV) patterns in high and low SIGLEC15 mRNA expression subgroups; some vital DNA damage repair deficiency scores addressed a negative correlation with SIGLEC15 mRNA expression. We also found that some commonly used chemotherapy drugs might be suitable for different SIGLEC15 mRNA expression subgroups. This study highlighted the vital role of SIGLEC15 in THCA. Targeting SIGLEC15 may offer a potential novel therapeutic opportunity for THCA patients. However, the detailed exact cellular mechanisms of SIGLEC15 in THCA still needed to be elucidated by further studies.

Monocytes maintain central nervous system homeostasis following helminth-induced inflammation

Neuroimmune interactions are crucial for regulating immunity and inflammation. Recent studies have revealed that the central nervous system (CNS) senses peripheral inflammation and responds by releasing molecules that limit immune cell activation, thereby promoting tolerance and tissue integrity. However, the extent to which this is a bidirectional process, and whether peripheral immune cells also promote tolerance mechanisms in the CNS remains poorly defined. Here we report that helminth-induced type 2 inflammation promotes monocyte responses in the brain that are required to inhibit excessive microglial activation and host death. Mechanistically, infection-induced monocytes express YM1 that is sufficient to inhibit tumor necrosis factor production from activated microglia. Importantly, neuroprotective monocytes persist in the brain, and infected mice are protected from subsequent lipopolysaccharide-induced neuroinflammation months after infection-induced inflammation has resolved. These studies demonstrate that infiltrating monocytes promote CNS homeostasis in response to inflammation in the periphery and demonstrate that a peripheral infection can alter the immunologic landscape of the host brain.

An Ex Vivo Organotypic Culture Platform for Functional Interrogation of Human Appendiceal Cancer Reveals a Prominent and Heterogenous Immunological Landscape.

Epithelial neoplasms of the appendix are difficult to study preclinically given their low incidence, frequent mucinous histology, and absence of a comparable organ in mice for disease modeling. Although surgery is an effective treatment for localized disease, metastatic disease has a poor prognosis as existing therapeutics borrowed from colorectal cancer have limited efficacy. Recent studies reveal that appendiceal cancer has a genomic landscape distinct from colorectal cancer and thus preclinical models to study this disease are a significant unmet need. We adopted an ex vivo slice model that permits the study of cellular interactions within the tumor microenvironment. Mucinous carcinomatosis peritonei specimens obtained at surgical resection were cutoff using a vibratome to make 150-μm slices cultured in media. Slice cultures were viable and maintained their cellular composition regarding the proportion of epithelial, immune cells, and fibroblasts over 7 days. Within donor specimens, we identified a prominent and diverse immune landscape and calcium imaging confirmed that immune cells were functional for 7 days. Given the diverse immune landscape, we treated slices with TAK981, an inhibitor of SUMOylation with known immunomodulatory functions, in early-phase clinical trials. In 5 of 6 donor samples, TAK981-treated slices cultures had reduced viability, and regulatory T cells (Treg). These data were consistent with TAK981 activity in purified Tregs using an in vitro murine model. This study demonstrates an approach to study appendiceal cancer therapeutics and pathobiology in a preclinical setting. These methods may be broadly applicable to the study of other malignancies.

Molecular Crosstalk between T Cells and Tumor Uncovers GBM-Specific T Cell Signatures in Blood: Noninvasive GBM Diagnosis Using Immunosensors.

Glioblastoma (GBM) is the most common and aggressive stage IV brain cancer with a poor prognosis and survival rate. The blood-brain barrier (BBB) in GBM prevents the entry and exit of biomarkers, limiting its treatment options. Hence, GBM diagnosis is pivotal for timely clinical management. Currently, there exists no clinically validated biomarker for GBM diagnosis. T cells exhibit the potential to escape a leaky BBB in GBM patients. These T cells infiltrating the GBM interact with the heterogeneous population of tumor cells, display a symbiotic interaction resulting in intertwined molecular crosstalk, and display a GBM-associated signature while entering the peripheral circulation. Therefore, we hypothesize that studying these distinct molecular changes is critical to enable T cells to be a diagnostic marker for accurate detection of GBM from patient blood. We demonstrated this by utilizing the phenotypic and immunological landscape changes in T cells associated with glioblastoma tumors. GBM exhibits a high level of heterogeneity with diverse subtypes of cells within the tumor, enabling immune infiltration and different degrees of interactions with the tumor. To accurately detect these subtle molecular differences in T cells, we designed an immunosensor with a high detection sensitivity and repeatability. Hence in this study, we investigated the characteristic behavior of T cells to establish two preclinically validated biomarkers: GBM-associated T cells (GBMAT) and GBM stem cell-associated T cells (GSCAT). A comprehensive investigation was conducted by mimicking the tumor microenvironment in vitro by coculturing T cells with cancer cells and cancer stem cells to study the distinct variation in GBMAT and GSCAT. Preclinical investigation of T cells from GBM patient blood shows similar characteristics to our established biomarkers (GBMAT, GSCAT). Further evaluating the relative attributes of T cells in patient blood and tissue biopsy confirms the infiltrating ability of T cells across the BBB. A pilot validation using a SERS-based machine learning algorithm was accomplished by training the model with GBMAT and GSCAT as diagnostic markers. Using GBMAT as a biomarker, we achieved a sensitivity and specificity of 93.3% and 97.4%, respectively, whereas applying GSCAT yielded a sensitivity and specificity of 100% and 98.7%, respectively. We also validated this diagnostic methodology by using conventional biological assays to study the change in expression levels of T cell surface markers (CD4 and CD8) and cytokine levels in T cells (IL6, IL10, TNFα, INFγ) from GBM patients. This study introduces T cells as GBM-specific immune biomarkers to diagnose GBM using patient liquid biopsy. This preclinical validation study presents a better translatability into clinical reality that will enable rapid and noninvasive glioblastoma detection from patient blood.

Clinical implication and immunological landscape analyses of ANLN in pan-cancer: A new target for cancer research.

Anillin is a F-actin binding protein (ANLN) mainly involved in the process of cytokinesis and known to be dysregulated in diverse cancers. However, the role of ANLN in pan-cancer prognosis and tumor immunity remains unclear. Gene expression profiles of 31 solid tumors were downloaded from The Cancer Genome Atlas (TCGA) database. ANLN mRNA and protein expression were quantified using quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). Protein expression of ANLN was further confirmed in Human Protein Atlas (HPA) database. Cox regression and Kaplan-Meier analysis were utilized to assess the prognostic value of ANLN in pan-cancer. The correlation between ANLN and different immune gene markers and infiltration cells was analyzed via ESTIMATE and CIBERSORT. A BLCA immunotherapy cohort: IMvigor (210) was used to confirm the role of ANLN in immune response. ANLN upregulation was detected in 21 types of cancers and was associated with poor overall survival (OS), disease-free interval (DFI), and progression-free interval (PFI) in most cancers except in THYM (Thymoma). Additionally, correlation analysis revealed a significantly positive association between ANLN expression and tumor mutation burden (TMB), microsatellite instability (MSI), immune cells infiltration. and immune checkpoint genes in various cancers. The BLCA immunotherapy cohort confirmed that patients with higher ANLN level had better immune responses and longer OS. ANLN may serve as a prognostic biomarker for pan-cancer. ANLN upregulation is associated with higher TMB, MSI, and immune cell infiltration in multiple types of tumors, shedding new light for cancer treatment.

Characterization of the Tumor Microenvironment in Osteosarcoma Identifies Prognostic- and Immunotherapy-Relevant Gene Signatures.

The osteosarcoma (OS) microenvironment is composed of tumor cells, immune cells, and stromal tissue and is emerging as a pivotal player in OS development and progression. Thus, microenvironment-targeted strategies are urgently needed to improve OS treatment outcomes. Using principal component analysis (PCA), we systematically examined the tumor microenvironment (TME) and immune cell infiltration of 88 OS cases and constructed a TME scoring system based on the TMEscore high and TMEscore low phenotypes. Our analysis revealed that TMEscore high correlates with longer survival in OS patients, elevated immune cell infiltration, increased immune checkpoints, and increased sensitivity to chemotherapy. TMEscore low strongly correlated with immune exclusion. These observations were externally validated using a GEO dataset (GSE21257) from 53 OS patients. Our laboratory data also proved our findings. This finding enhances our understanding of the immunological landscape in OS and may uncover novel targeted therapeutic strategies.

Single-cell analyses reveal early thymic progenitors and pre-B cells in zebrafish.

The zebrafish has proven to be a valuable model organism for studying hematopoiesis, but relatively little is known about zebrafish immune cell development and functional diversity. Elucidating key aspects of zebrafish lymphocyte development and exploring the breadth of effector functions would provide valuable insight into the evolution of adaptive immunity. We performed single-cell RNA sequencing on ∼70,000 cells from the zebrafish marrow and thymus to establish a gene expression map of zebrafish immune cell development. We uncovered rich cellular diversity in the juvenile and adult zebrafish thymus, elucidated B- and T-cell developmental trajectories, and transcriptionally characterized subsets of hematopoietic stem and progenitor cells and early thymic progenitors. Our analysis permitted the identification of two dendritic-like cell populations and provided evidence in support of the existence of a pre-B cell state. Our results provide critical insights into the landscape of zebrafish immunology and offer a foundation for cellular and genetic studies.

The Long and Winding Road: An Overview of the Immunological Landscape of Intracranial Meningiomas.

Simple SummaryThe tumor microenvironment represents the essential basis for characterizing oncological cells and supporting their growth. Along with genomic sequencing, the study of the tumor microenvironment represents a big step forward in oncological research and in the customization of treatments. Compared to gliomas, for which research has discovered greater results, the correlation between the microenvironment and tumor phenotype, and consequent prognostic implications, are still incompletely understood for intracranial meningioma. Recently, studies about the immunogenetic landscape of meningiomas have been promoted, and it is now clear that understanding the multifactorial pathogenesis of meningioma and its correlation with other specific signs (i.e., PTBE) could lead to the development of new targeted therapies, and significantly affect meningioma patients’ prognosis.The role of immunotherapy is gaining ever-increasing interest in the neuro-oncological field, and this is also expanding to the management of intracranial meningioma. Meningiomas are still the most common primary adult tumor of the CNS, and even though surgery and/or radiotherapy still represent cornerstones of their treatment, recent findings strongly support the potential role of specific immune infiltrate cells, their features and genomics, for the application of personalized treatments and prognostic implications. According to the PRISMA guidelines, systematic research in the most updated platform was performed in order to provide a descriptive and complete overview about the characteristics, role and potential implications of immunology in meningioma tumors. Seventy articles were included and analyzed in the present paper. The meningioma microenvironment reveals complex immune tumor-immune cells interactions that may definitely influence tumor progression, as well as offering unexpected opportunities for treatment.

Identification of a Novel Tumor Inflammation Signature for Risk Stratification, Prognosis Prediction, and Immune Status in Colorectal Cancer.

Background Inflammation and immune cell dysfunction have been widely known as an essential role in the tumorigenesis of colorectal cancer (CRC). Yet, the role of tumor inflammation signature (TIS) associated with CRC prognosis, immune infiltration, and drug resistance remained unknown. Method The transcriptome sequencing data, as well as clinical data of CRC from the public dataset, were acquired for further investigation. Inflammation-related gene expression patterns were obtained and analyzed. Bioinformatics methods were used to build a prognostic TIS, and its prediction accuracy was verified by using ROC curve analyses. The independent prognostic factors in CRC were identified through multivariable Cox regression analysis. In addition, the specific features of the immunological landscape between low- and high-risk CRC cohorts were analyzed. Results We firstly screened the differentially expressed inflammation-related genes in CRC and constructed a prognostic TIS. We further classified CRC patients into high or low TIS score groups based on the optimal cutoff of prognostic TIS, and patients with high-risk scores had shorter overall survival (OS) than those in the low-risk cohort. The diagnostic accuracy of TIS was evaluated and confirmed with ROC analysis. The result of the univariate and multivariate analysis found that TIS was directly and independently linked to OS of CRC. Otherwise, an optimal nomogram model based on TIS exhibited a better prognostic accuracy in OS. Finally, the immunological status and immune cell infiltration were observed different in the two-risk cohorts. Conclusion In summary, the risk model of the TIS in CRC was found to be useful for predicting patient prognosis and guiding individual treatment. This risk signature could also serve as potential biomarkers and immunotherapeutic targets and indicate immunotherapy response for patients with CRC.

Lactate Metabolism-Associated lncRNA Pairs: A Prognostic Signature to Reveal the Immunological Landscape and Mediate Therapeutic Response in Patients With Colon Adenocarcinoma.

BackgroundLactate metabolism is critically involved in the tumor microenvironment (TME), as well as cancer progression. It is important to note, however, that lactate metabolism-related long non-coding RNAs (laRlncRNAs) remain incredibly understudied in colon adenocarcinoma (COAD).MethodsA gene expression profile was obtained from the Cancer Genome Atlas (TCGA) database to identify laRlncRNA expression in COAD patients. A risk signature with prognostic value was identified from TCGA and Gene Expression Omnibus (GEO) cohort based on laRlncRNA pairs by the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and functional experiments were carried out to verify the expression of laRlncRNAs in COAD. The relationship of laRlncRNA pairs with immune landscape as well as the sensitivity of different therapies was explored.ResultsIn total, 2378 laRlncRNAs were identified, 1,120 pairs of which were studied to determine their prognostic validity, followed by a risk signature established based on the screened 5 laRlncRNA pairs. The laRlncRNA pairs-based signature provided a better overall survival (OS) prediction than other published signatures and functioned as a prognostic marker for COAD patients. According to the calculated optimal cut-off point, patients were divided into high- and low-risk groups. The OS of COAD patients in the high-risk group were significantly shorter than that of those in the low-risk group (P=4.252e-14 in the TCGA cohort and P=2.865-02 in the GEO cohort). Furthermore, it remained an effective predictor of survival in strata of gender, age, TNM stage, and its significance persisted after univariate and multivariate Cox regressions. Additionally, the risk signature was significantly correlated with immune cells infiltration, tumor mutation burden (TMB), microsatellite instability (MSI) as well as immunotherapeutic efficacy and chemotherapy sensitivity. Finally, one of the laRlncRNA, LINC01315, promotes proliferation and migration capacities of colon cancer cells.ConclusionThe newly identified laRlncRNAs pairs-based signature exhibits potential effects in predicting prognosis, deciphering patients’ immune landscape, and mediating sensitivity to immunotherapy and chemotherapy. Findings in our study may provide evidence for the role of laRlncRNAs pairs as novel prognostic biomarkers and potentially individualized therapy targets for COAD patients.

Immunological Landscape of HER-2 Positive Breast Cancer.

Simple SummaryThe aim of this work is to elucidate the role of immune response in HER2+ breast cancer. By describing the principal components of the tumour microenvironment and its interaction with the known and novel anti-HER2 targeted therapies, this review summarizes the ways immune modulators could be implemented in clinical practice.Understanding the biological aspects of immune response in HER2+ breast cancer is crucial to implementing new treatment strategies in these patients. It is well known that anti-HER2 therapy has improved survival in this population, yet a substantial percentage may relapse, creating a need within the scientific community to uncover resistance mechanisms and determine how to overcome them. This systematic review indicates the immunological mechanisms through which trastuzumab and other agents target cancer cells, also outlining the main trials studying immune checkpoint blockade. Finally, we report on anti-HER2 vaccines and include a figure exemplifying their mechanisms of action.

Abstract 644: Deep learning-based H&E analyzer reveals distinct immune profiles and clinical outcomes among immune phenotypes in uterine corpus endometrial carcinoma

Abstract Introduction: Deep learning-based H&E analyzer can classify the tumor microenvironment as three immune phenotypes: the immune-inflamed, excluded and desert. Our previous study demonstrated a distinct transcriptomic and immunologic landscape amongst the phenotypes in non-small cell lung cancer (NSCLC). However, it has not been fully investigated in other cancers. Here, we explore the immune profiles and clinical outcomes between the three immune phenotypes in uterine corpus endometrial carcinoma (UCEC). Methods: Tissue H&E slide images, sequencing data, and clinical data were utilized from The Cancer Genome Atlas (TCGA). Lunit-SCOPE IO was trained with multi-cancer 3,166 H&E whole slide images annotated by pathologists. Based on the proportion of tumor infiltrating lymphocytes (TIL) highly conserved either in cancer epithelium (CE) or cancer stroma (CS), Lunit-SCOPE IO classifies tumors as immune-inflamed and excluded, respectively. Also, it classifies tumors with low TIL density in CE and CS as immune-desert. Results: Among 486 patients with UCEC, the frequency of immune-inflamed, excluded and desert was 174 (35.8%), 160 (32.9%), and 156 (32%), respectively. In the three subgroup comparison, immune-inflamed was associated with the best survival outcome and -excluded was associated with the worst survival outcome (Inflamed vs excluded, HR 0.30 95% CI 0.17-0.55, p<.001; desert vs excluded, HR 0.50 95% CI 0.30-0.84, p=0.009). Likewise, inflamed subtype showed better overall survival (HR 0.43, 95% CI 0.25-0.75, p=0.003) compared to others. In microsatellite instability high (MSI-H) tumors, we observed a similar tendency of improved overall survival in the tumors of inflamed subtype, both compared to the excluded subtype and to a combination of other subtypes. (Inflamed vs excluded, HR 0.18 95% CI 0.05-0.73, p=0.017; inflamed vs others, HR 0.21 95% CI 0.06-0.72, p=0.014). Immune-inflamed had significantly higher cytolytic activity (Inflamed 7.25 vs others 6.34, p<.001) and was associated with higher PD-L1 expression (Inflamed 19.03 vs others 10.7, p=0.003) and CTLA4 expression (Inflamed 60.62 vs others 31.5, p<.001). Immune-inflamed had a higher proportion of CD8 positive T cell (Inflamed 16.7% vs 12.8%, p<.001) and M1 macrophage (Inflamed 3.9% vs others 2.8%, p<.001) and a lower proportion of M2 macrophage (Inflamed 15% vs others 17.9%, p<.001). Conclusion: The three tissue phenomic subtypes showed distinct immune profiles and clinical outcomes, with immune-inflamed having the best overall survival outcome. In particular, non-inflamed group was associated with worse overall survival even in MSI-H tumors deemed to have more favorable prognosis compared to MSS tumors. Given the definite differences in the survival outcome, tissue H&E based tumor microenvironment classification may serve as a potential prognostic biomarker in UCEC. Citation Format: Horyun Choi, Leeseul Kim, Jinah Kim, Yeun Ho Lee, Hyung-Gyo Cho, Na Hyun Kim, Gahyun Gim, Sanghoon Song, Gahee Park, Soo Ick Cho, Sergio Pereira, Donggeun Yoo, Kyunghyun Paeng, Chan-Young Ock, Young Kwang Chae. Deep learning-based H&E analyzer reveals distinct immune profiles and clinical outcomes among immune phenotypes in uterine corpus endometrial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 644.

Nisin probiotic prevents inflammatory bone loss while promoting reparative proliferation and a healthy microbiome

Dysbiosis of the oral microbiome mediates chronic periodontal disease. Realignment of microbial dysbiosis towards health may prevent disease. Treatment with antibiotics and probiotics can modulate the microbial, immunological, and clinical landscape of periodontal disease with some success. Antibacterial peptides or bacteriocins, such as nisin, and a nisin-producing probiotic, Lactococcus lactis, have not been examined in this context, yet warrant examination because of their biomedical benefits in eradicating biofilms and pathogenic bacteria, modulating immune mechanisms, and their safety profile in humans. This study’s goal was to examine the potential for nisin and a nisin-producing probiotic to abrogate periodontal bone loss, the host inflammatory response, and changes in oral microbiome composition in a polymicrobial mouse model of periodontal disease. Nisin and a nisin-producing Lactococcus lactis probiotic significantly decreased the levels of several periodontal pathogens, alveolar bone loss, and the oral and systemic inflammatory host response. Surprisingly, nisin and/or the nisin-producing L. lactis probiotic enhanced the population of fibroblasts and osteoblasts despite the polymicrobial infection. Nisin mediated human periodontal ligament cell proliferation dose-dependently by increasing the proliferation marker, Ki-67. Nisin and probiotic treatment significantly shifted the oral microbiome towards the healthy control state; health was associated with Proteobacteria, whereas 3 retroviruses were associated with disease. Disease-associated microbial species were correlated with IL-6 levels. Nisin or nisin-producing probiotic’s ability to shift the oral microbiome towards health, mitigate periodontal destruction and the host immune response, and promote a novel proliferative phenotype in reparative connective tissue cells, addresses key aspects of the pathogenesis of periodontal disease and reveals a new biomedical application for nisin in treatment of periodontitis and reparative medicine.