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Natural killer (NK) cells are innate immune cells that are critical to the body's antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.

Antibody-drug conjugates (ADCs) have emerged as a revolutionary therapeutic class, combining the precise targeting ability of monoclonal antibodies with the potent cytotoxic effects of chemotherapeutics. Notably, ADCs have rapidly advanced in the field of breast cancer treatment. This innovative approach holds promise for strengthening the immune system through antibody-mediated cellular toxicity, tumor-specific immunity, and adaptive immune responses. However, the development of upfront and acquired resistance poses substantial challenges in maximizing the effectiveness of these therapeutics, necessitating a deeper understanding of the underlying mechanisms. These mechanisms of resistance include antigen loss, derangements in ADC internalization and recycling, drug clearance, and alterations in signaling pathways and the payload target. To overcome resistance, ongoing research and development efforts are focused on urgently identifying biomarkers, integrating immune therapy approaches, and designing novel cytotoxic payloads. This Review provides an overview of the mechanisms and clinical effectiveness of ADCs, and explores their unique immune-boosting function, while also highlighting the complex resistance mechanisms and safety challenges that must be addressed. A continued focus on how ADCs impact the tumor microenvironment will help to identify new payloads that can improve patient outcomes.

Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.

To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses. Fine tuning the immune response in line with the degree of threat is central to recognition of a pathogen versus commensal bacteria. Here the authors implicate a digital all-or-nothing cell response in control of the tissue level immune response.

Background The Dallas Metastatic Cancer Study is a clinical database established to examine local trends associated with the diagnosis and treatment of de novo metastatic breast cancer and identify factors for further evaluation. Clinical characteristics of patients with de novo metastatic breast cancer are often underreported in the literature. Methods We report data from 2010 to 2021 for patients with de novo metastatic breast cancer along with the impact of clinical variables such as age, BMI, race and ethnicity, insurance status, hypertension, diabetes, and site of metastasis with survival analysis with respect to subtype. Results Black race (HR 2.07, 95% CI 1.56–2.74), public insurance (HR 1.64, 95% CI 1.23–2.18), no insurance (HR 1.69, 95% CI 1.24–2.31), hypertension (HR 1.50, 95% CI 1.18–1.91), diabetes (HR 1.69, 95% CI 1.24–2.31), and visceral metastases including brain (HR 1.68, 95% CI 1.20–2.36), liver (HR 1.80, 95% CI 1.40–2.30), and lung (HR 1.50, 95% CI 1.17–1.92) were associated with increased mortality and remained significant when controlled for subtype. In the multivariate analysis, diabetes (HR 1.74, 95% CI 1.22–2.49) and presence of liver metastases (HR 1.97, 95% CI 1.43–2.49) remained independently associated with decreased overall survival regardless of subtype and other variables. Patients diagnosed at 40 and younger were less likely to have hypertension and diabetes, more likely to be Hispanic, and showed distinct subtype distributions compared to those diagnosed at older ages. Conclusions Future work will focus on these associations at the patient level to identify targets for intervention. Plain language summary The Dallas Metastatic Cancer Study aims to better understand metastatic breast cancer by examining local trends in diagnosis and treatment. The study analyzed data from 2010 to 2021 and specifically focused on patients with a metastatic breast cancer diagnosis at first presentation. The study evaluated how factors such as age, BMI, race, insurance status, and co-existing medical conditions like hypertension and diabetes affected survival. The results show that Black patients, those with public or no insurance, those with specific metastases (i.e., liver, brain, lung) had worse survival outcomes. These outcomes underscore the areas where targeted interventions could improve patient outcomes. Chang, Cao et al. examine local trends associated with the diagnosis and treatment of de novo metastatic breast cancer. Findings show that black race, hypertension, diabetes, as well as the presence of visceral metastases are associated with a worse prognosis.

Involving patient advocates as partners in cancer research improves research and provides favorable experiences for both the researcher and the advocate. Previous work demonstrates challenges to establishing relationships between researchers and advocates, including uncertainty about why the relationships are necessary, how to establish them, what to say, and how they should be structured. To overcome these challenges, we established the Metastatic Breast Cancer Research Conference (MBCRC) Advocate Researcher Program (MARP) at the MBCRC in 2023. We outline the approach to the program to serve as a model for others interested in performing similar activities and report findings from surveys to establish evidence about the value of these relationships. The program connected 21 pairs of researchers and advocates, and participants responded to surveys about their experience, largely describing positive outcomes. Our hope is that a program like this could be used at any cancer conference in the future as we continue to encourage advocates and researchers to work together.

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications (CNA). CNA are genetic alterations that are increasingly becoming relevant to breast oncology clinical practice. Here we identify CNA in metastatic breast tumor samples using publicly available datasets and characterize their expression and function using a metastatic mouse model of breast cancer. Our findings demonstrate that our organoid generation can be implemented to study clinically relevant features that reflect the genetic heterogeneity of individual tumors.

Including patient advocates in basic cancer research ensures that breast cancer research is intentional, supports effective communication with broader audiences, and directly connects researchers with those who they are striving to help. Despite this utility, many cancer research scientists do not work with patient advocates. To understand barriers to engagement and build a framework for enhanced interactions in the future, we hosted a workshop with patient advocates and researchers who do engage, then discussed findings at an international metastatic breast cancer conference to solicit additional feedback and suggestions. Findings demonstrate that researchers are uncertain about how to initiate and maintain relationships with advocates. We offer actionable steps to support researchers working with patient advocates to improve cancer research and accomplish our collective goal of improving lives of those who have been diagnosed with breast cancer. We hope that this initiative will facilitate such collaborative efforts.

ObjectiveImmune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells.DesignThe hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans.ResultsWhen fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18‒/‒ and CD1d‒/‒ mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity.ConclusionHepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis.

Purpose Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. Methods 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. Results Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1 + expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4 + , CD8 + , and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. Conclusions LvMs are less likely to express PD-L1 + tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.