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Conventional APCs that express MHC class II (MHCII) and co‐stimulatory molecules include dendritic cells (DCs) and macrophages. Beyond these conventional APCs, immune stimulatory cells have been more recently shown to extend to a class of atypical APCs, composed of mast cells, basophils, and eosinophils. Here, we describe a unique type of APC, Gr1−/lowCD11b−/low cells with a granularity and size characteristic of myeloid cells and with the ability to present Ag for crosspresentation. These cells constitutively express MHCII and the costimulatory molecules, CD80, CD86, and CD40. They do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C), or macrophages (F4/80), and their frequency is inversely correlated with myeloid‐derived suppressor cells (MDSCs) in tumor‐bearing mice. Among splenocytes, they are more abundant than DCs and macrophages, and they exhibit antitumor immune stimulatory function at a steady state without further activation, ex vivo. They are also found within the tumor bed where they retain their immune stimulatory function. Our findings suggest the use of these novel APCs in additional preclinical studies to further investigate their utility in APC‐based cancer immunotherapies. A new class of antigen presenting cells that are able to boost anti‐tumor immune responses is described. [ABSTRACT FROM AUTHOR]

Background: Recent observations suggest that immune-mediated tissue destruction is dependent upon coordinate activation of immune genes expressed by cells of the innate and adaptive immune systems. Methods: Here, we performed a retrospective pilot study to investigate whether the coordinate expression of molecular signature mostly associated with NK cells could be used to segregate breast cancer patients into relapse and relapse-free outcomes. Results: By analyzing primary breast cancer specimens derived from patients who experienced either 58- 116 months (∼5-9 years) relapse-free survival or developed tumor relapse within 9-76 months (∼1-6 years) we found that the expression of molecules involved in activating signaling of NK cells and in NK cells: target interaction is increased in patients with favorable prognosis. Conclusions: The parameters identified in this study, together with the prognostic signature previously reported by our group, highlight the cooperation between the innate and adaptive immune components within the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Summary: Women classified as having triple-negative tumors have a poor prognosis. The importance of CD44+/CD24−/low (stem/progenitor cell-phenotype) in breast cancer patients has also been appreciated. However, correlation between triple negativity and CD44+/CD24−/low with tumor recurrence remains elusive. In the present study, we evaluated tumor specimens of 50 breast cancer patients with known hormone receptor status for whom we had follow-up information and outcome data available, and performed immunohistochemistry analysis to determine CD44 and CD24 expression. Gene expression arrays were also independently performed on 52 breast cancer specimens with banked frozen tissue. Lastly, we used FVBN202 transgenic mouse model of breast carcinoma and determined the hormone receptor status, the proportion of CD44+/CD24−/low breast cancer stem-like cells, and the behavior of the tumor. We determined that patients with triple-negative tumors had significantly higher incidence of recurrence or distant metastasis associated with increased frequency of breast cancer stem cell phenotypes compared with those with non–triple-negative tumors. Preclinical studies in FVBN202 transgenic mice confirmed these findings by showing that relapsed tumors were triple negative and had significantly higher frequency of breast cancer stem cells compared with their related primary tumors. Unlike non–triple-negative primary tumors, relapsed triple-negative tumors were tumorigenic at low doses when inoculated into FVBN202 transgenic mice. These findings suggest that CD44+/CD24−/low breast cancer stem-like cells play an important role in the clinical behavior of triple-negative breast cancer and that development of therapeutic targets directed to breast cancer stem-like cells may lead to reduction in the aggressiveness of triple-negative breast cancers. [ABSTRACT FROM AUTHOR]

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8+ > CD4+, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8+ = CD4+, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner. [Display omitted] • A multi-dimensional analysis reveals distinct immunological patterns inhibiting HCC • Predominant Th1, but not Th17, inflammatory pattern promotes HCC • An equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern in the liver inhibits HCC Mirshahi et al. performed a three-dimensional analysis of hepatic and splenic immune cells, correlating the immune cell types, their interactions and proportions, and changes over time. They discover gender-associated immunological patterns determining tumor progression, as well as partial or complete inhibition of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

The article discusses a case of a 55-year-old woman who were found to have an oval hypoechoic mass on her left breast. A core needle biopsy demonstrated obliteration of the breast by a dense lymphocytic infiltrates within which isolated and small clusters of pleomorphic epithelial cells were found. Based on the findings, the patient was diagnosed with invasive carcinoma with features of lymphoepithelioma-like carcinoma (LELC) and subsequently underwent excision of the lesion.

Background: Although breast cancer mortality is a result of distant recurrences associated with the establishment of tumor dormancy, current clinical practice guidelines recommend a wait and watch approach for tumor recurrences. This is because of our limited understanding of tumor dormancy and insufficient evidence in support of immunological control of tumor dormancy.Methods: We used FVBN202 transgenic mice expressing rat neu oncogene in the mammary glands, and their parental FVB strain lacking neu expression. These models allowed the detection of tumor dormancy at distant sites using the rat neu protein as a tumor marker. We also used Ki67 for the detection of the indolent and quiescent types of tumor dormancy. Multicolor flow cytometry was used to detect dormant tumor cells and T cell subsets. Co-culture studies were performed to determine the role of T cells in preventing regrowth of dormant cells.Results: We demonstrated that dormant tumor cells were present at the site of primary breast cancer and at distant sites in the lungs and in the liver very early in the course of early stage breast cancer when no distant metastasis was evident. Dormant tumor cells were characterized as neu expressing Ki67- and Ki67low fractions associated with the induction of local immune responses predominated by CD4+ and CD8+ T effector cell subsets. The presence of neu-autoreactive T cells from FVBN202 mice only prevented regrowth of dormant cells. On the other hand, presence of neu-alloreactive anti-tumor T cells in FVB mice prior to tumor challenge resulted in the protection of mice from the dissemination of dormant tumor cells to distant organs.Conclusion: Our results suggest that immunotherapeutic targeting of semi-allogeneic mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease. [ABSTRACT FROM AUTHOR]

The recent progresses in understanding of cancer glycolytic phenotype have offered new strategies to manage ovarian cancer and other malignancies. However, therapeutic targeting of glycolysis to treat cancer remains unsuccessful due to complex mechanisms of tumor glycolysis and the lack of selective, potent and safe glycolytic inhibitors. Recently, BAY-876 was identified as a new-generation inhibitor of glucose transporter 1 (GLUT1), a GLUT isoform commonly overexpressed but functionally poorly defined in ovarian cancer. Notably, BAY-876 has not been evaluated in any cell or preclinical animal models since its discovery. We herein took advantage of BAY-876 and molecular approaches to study GLUT1 regulation, targetability, and functional relevance to cancer glycolysis. The anti-tumor activity of BAY-876 was evaluated with ovarian cancer cell line- and patient-derived xenograft (PDX) models. Our results show that inhibition of GLUT1 is sufficient to block basal and stress-regulated glycolysis, and anchorage-dependent and independent growth of ovarian cancer cells. BAY-876 dramatically inhibits tumorigenicity of both cell line-derived xenografts and PDXs. These studies provide direct evidence that GLUT1 is causally linked to the glycolytic phenotype in ovarian cancer. BAY-876 is a potent blocker of GLUT1 activity, glycolytic metabolism and ovarian cancer growth, holding promise as a novel glycolysis-targeted anti-cancer agent. [ABSTRACT FROM AUTHOR]

Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of focusing on detailed specific cell types and missing the collective function of the hepatic immune system. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC. [ABSTRACT FROM AUTHOR]

Background There are no effective treatments for pancreatic cancer peritoneal carcinomatosis (PC) or cancer dissemination in abdominal cavity. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays critical roles in cancer progression. We reported that SphK1, but not SphK2, is responsible for S1P export from breast cancer cells and recently discovered that S1P is linked to inflammation and cancer in colitis-associated cancer progression. Given the fact that inflammation is known to be essential for the establishment and progression of PC, we hypothesized that SphK1 in the host animals is involved in progression of pancreatic cancer PC. Methods Murine pancreatic adenocarcinoma panc02-luc cells were intraperitoneally injected into wildtype or SphK1 knockout (KO) mice to generate a syngeneic PC model. Cell proliferation and apoptosis were determined by Ki67 and TUNEL staining, respectively. Results All the animals developed panc02-luc PC. SphK1 KO mice developed significantly less tumor burden, less total tumor weight, and fewer number of PC nodules at 14 d after implantation. Histologically, less inflammatory cell infiltration and less cancer cell proliferation were observed in the tumors. There was no difference in apoptosis. Conclusions Our results raise an intriguing possibility that S1P generated by SphK1 in the host promotes pancreatic cancer PC progression by stimulation of proliferation of cancer cells. [ABSTRACT FROM AUTHOR]

Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells., Competing Interests: Competing interests: All authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background & Aims: Intra and inter-pathologist variability poses a significant challenge in metabolic dysfunction-associated steatohepatitis (MASH) biopsy evaluation, leading to suboptimal selection of patients and confounded assessment of histological response in clinical trials. We evaluated the utility of an artificial intelligence (AI) digital pathology (DP) platform to aid pathologists improve the reliability of fibrosis staging., Methods: A total of 120 digitized histology slides from two trials (NCT03517540, NCT03912532) were analysed by four expert hepatopathologists, with and without AI-assistance in a randomized, cross-over design. We utilized the HistoIndex AI DP platform, consisting of unstained second harmonic generation/two photon excitation fluorescence (SHG/TPEF) images and AI quantitative fibrosis (qF) values., Results: AI-assistance significantly improved inter-pathologist kappa for fibrosis (F)-staging, particularly for early fibrosis (F0-F2), with reduced variance around the median reads. Intra-pathologist kappa was unchanged. AI-assistance increased pathologist concordance for identifying clinical trial inclusion subjects (F2-F3) from 45% to 71%, exclusion subjects (F0/F1/F4) from 38% to 55%, and evaluation of fibrosis response to treatment from 49% to 61%. SHG/TPEF images, qFibrosis continuous values, and qF-stage were considered useful by at least 3 out of 4 pathologists in 83%, 55%, and 38% cases, respectively. In the context of a clinical trial, the increase in inter-pathologist concordance in this study is modeled to result in a ∼25% reduction in the potential need for adjudication as well as a ∼50% increase in the study power., Conclusions: The use of AI DP enhances inter-rater reliability of fibrosis staging for MASH. This indicates that the SHG/TPEF-based AI DP tool is useful for assisting pathologists in assessing fibrosis, thereby enhancing clinical trial efficiency and reliability of fibrosis readouts in response to treatments., Competing Interests: Declaration of Competing Interest DA, CKW, AS, RK, TF, AR, ST, CLC, RB, SSE, AABA are employees and stockholders of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA at the time of the study. CZLO, YZ, CH, are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway. SL, EC, DT, GH are employees of HistoIndex Pte. Ltd. AJS has served as a consultant to Histoindex, Gilead, Intercept, Merck, Eli Lilly, Novo Nordisk, Pfizer, Astra Zeneca, Boehringer Ingelhiem, Madrigal, Novartis, Genentech, Roche, Hanmi, Sequana, Bard, Alnylam, Regeneron, Poxel, Surrozen, Avant Sante, Amgen, Path AI, Myovant, Aligos, Promed, Rona. His institution has received grants from Gilead, Madrigal, Salix, Novo Nordisk, Eli Lilly, Hanmi, Bristol Myers Squibb, Echosens. He has stock options in Genfit, Tiziana, Durect, Inversago, Indalo, Northsea, Rivus. He received royalties from Wolter Kluwers and Elsevier. MOI has served as a consultant for, or received speakers' fees from Path AI, Clinnovate Health, and Target RWE. He has received grants from the National Institutes of Health (NIH) and the National Cancer Institute (NCI). TJK has served as a consultant for, or received speakers' fees from Resolution Therapeutics, Clinnovate Health, HistoIndex, Servier Laboratories, Fibrofind, Kynos Therapeutics, Perspectum Diagnostics, Concept Life Sciences, Jazz Pharmaceuticals and Incyte Corporation. AW, GS, MOI and TJK received a fee-for-service from Clinnovate Health as expert pathologists in this study. DEK discloses no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The liver hosts a diverse array of immune cells that play pivotal roles in both maintaining tissue homeostasis and responding to disease. However, the precise contributions of these immune cells in the progression of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) remain unclear. Utilizing a systems immunology approach, we reveal that liver immune responses are governed by a dominant-subdominant hierarchy of ligand-receptor-mediated homeostatic pathways. In healthy individuals, inflammatory immune responses operate within these pathways, challenging the notion of the liver as a purely tolerogenic organ. Chronic consumption of a Western diet (WD) disrupts hepatocyte function and reconfigures immune interactions, resulting in hepatic stellate cells (HSCs), cancer cells, and NKT cells driving 80% of the immune activity during NAFLD. In HCC, 80% of immune response involves NKT cells and monocytes collaborating with hepatocytes and myofibroblasts to restore disrupted homeostasis. Interestingly, dietary correction during NAFLD yields nonlinear outcomes: tumor progression coincides with the failure of mounting homeostatic immune responses, whereas tumor prevention is associated with sustained immune responses, predominantly orchestrated by monocytes. These monocytes actively target fibroblasts and myofibroblasts, creating a tumor-suppressive microenvironment. Notably, only 5% of T cells displayed apoptosis-inducing activity, selectively contributing to the turnover of hepatic stromal cells, particularly myofibroblasts and fibroblasts. Our findings suggest that effective anti-tumor immune responses in the liver are primarily mediated by immune cells sustaining tissue homeostasis, rather than relying on direct cytotoxic mechanisms., Competing Interests: Authors’ Disclosures A.J.S. and F.M. hold a patent on the DIAMOND mouse model, PCT/US2016/056506. All other authors do not have any competing interest.