Fibroblast activation protein-α (FAP) is a type-II transmembrane serine protease expressed almost exclusively to pathological conditions including fibrosis, arthritis, and cancer. Across most cancer ...types, elevated FAP is associated with worse clinical outcomes. Despite the clear association between FAP and disease severity, the biological reasons underlying these clinical observations remain unclear. Here we review basic FAP biology and FAP’s role in non-oncologic and oncologic disease. We further explore how FAP may worsen clinical outcomes via its effects on extracellular matrix remodeling, intracellular signaling regulation, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. Lastly, we discuss the potential to exploit FAP biology to improve clinical outcomes.
Cancer immunotherapy has revolutionized cancer treatment, spurring extensive investigation into cancer immunology and how to exploit this biology for therapeutic benefit. Current methods to ...investigate cancer-immune cell interactions and develop novel drug therapies rely on either two-dimensional (2D) culture systems or murine models. However, three-dimensional (3D) culture systems provide a potentially superior alternative model to both 2D and murine approaches. As opposed to 2D models, 3D models are more physiologically relevant and better replicate tumor complexities. Compared to murine models, 3D models are cheaper, faster, and can study the human immune system. In this review, we discuss the most common 3D culture systems-spheroids, organoids, and microfluidic chips-and detail how these systems have advanced our understanding of cancer immunology.
Tumor response to therapy is affected by both the cell types and the cell states present in the tumor microenvironment. This is true for many cancer treatments, including immune checkpoint inhibitors ...(ICIs). While it is well-established that ICIs promote T cell activation, their broader impact on other intratumoral immune cells is unclear; this information is needed to identify new mechanisms of action and improve ICI efficacy. Many preclinical studies have begun using single-cell analysis to delineate therapeutic responses in individual immune cell types within tumors. One major limitation to this approach is that therapeutic mechanisms identified in preclinical models have failed to fully translate to human disease, restraining efforts to improve ICI efficacy in translational research.
We previously developed a computational transfer learning approach called projectR to identify shared biology between independent high-throughput single-cell RNA-sequencing (scRNA-seq) datasets. In the present study, we test this algorithm's ability to identify conserved and clinically relevant transcriptional changes in complex tumor scRNA-seq data and expand its application to the comparison of scRNA-seq datasets with additional data types such as bulk RNA-seq and mass cytometry.
We found a conserved signature of NK cell activation in anti-CTLA-4 responsive mouse and human tumors. In human metastatic melanoma, we found that the NK cell activation signature associates with longer overall survival and is predictive of anti-CTLA-4 (ipilimumab) response. Additional molecular approaches to confirm the computational findings demonstrated that human NK cells express CTLA-4 and bind anti-CTLA-4 antibodies independent of the antibody binding receptor (FcR) and that similar to T cells, CTLA-4 expression by NK cells is modified by cytokine-mediated and target cell-mediated NK cell activation.
These data demonstrate a novel application of our transfer learning approach, which was able to identify cell state transitions conserved in preclinical models and human tumors. This approach can be adapted to explore many questions in cancer therapeutics, enhance translational research, and enable better understanding and treatment of disease.
BackgroundPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because ...of PDAC’s extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, ‘cold’) tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.MethodsWe examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.ResultsIn both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.ConclusionsThese findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in ‘cold’ tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.
Medical school can be a socially isolating experience, particularly for students underrepresented in medicine. Social isolation and perceptions of not belonging can negatively impact students' ...academic performance and well-being. Therefore, interventions are needed to support students and these efforts should be appealing, brief, and low-burden.
Guided by evidence-based approaches, we developed the Build & Belong intervention for medical students as a brief peer-to-peer approach that consisted of four components. First, M3 and M4 students wrote reflections on belonging in medical school. Second, M3 and M4 students video recorded messages for M1 and M2 students using their written reflections. Third, M1 and M2 students watched and discussed the videos in small groups. Fourth, the M1 and M2 students wrote letters to future students. Our intervention differs from previous student belonging interventions in the peer delivery of messages.
The Build & Belong intervention aimed to improve medical students' social belongingness. Using a longitudinal observational study design, the intervention was piloted at a medical school in the Mid-Atlantic United States in 2017-2018. Students completed surveys before and after the intervention. Paired samples tests (t-tests and Wilcoxon) assessed pre- to post-intervention changes in social isolation, social connectedness, and social assurance.
Among 63 medical students, with 25.9% from backgrounds underrepresented in medicine, we assessed follow-up outcomes in 38 students. Social isolation scores significantly decreased from baseline (M = 54.8, SD = 7.06) to follow-up (M = 51.3, SD = 6.67; p < .001). Social isolation changes were evident regardless of sex, although males reported a greater reduction (M Δ = −5.32, p < .001) than females (M Δ = −2.79, p = .014). Black/African American students had the largest reduction in social isolation (M Δ = −7.24, p = .010). Social assurance and connectedness scores did not change significantly between baseline and follow-up. Medical students appeared to resonate with messages delivered by more experienced peers (M3s and M4s), particularly messages that normalized feelings of not belonging and strategies to reduce those feelings.
The Build & Belong intervention appears to reduce social isolation scores among medical students. This pilot test of the Build & Belong intervention provides initial evidence of the effectiveness of a brief, low-cost intervention. Build & Belong may provide a scalable strategy to reduce medical students' social isolation. Our peer-based approach is distinct from administrator-led strategies; peers were seen as trusted and reliable sources of information about belonging and ways to overcome the challenges experienced during medical school.
•We prospectively followed 122 women with singleton live births residing in Romania.•We measured arsenic in drinking water and abstracted data from delivery records.•Women were exposed to low levels ...of drinking water arsenic, mostly <10μg/L.•Higher arsenic associated with lower birth weight and shorter length among smokers.•Higher arsenic was associated with lower ponderal index in boys only.
Women are exposed to drinking water with low arsenic concentrations (<10.0μg/L) worldwide, yet little work has been done to assess the risk. To begin to address this data gap, we conducted an exploratory study of birth outcomes in Timis County, Romania. We prospectively followed 122 women with singleton deliveries, for whom we constructed individual exposure indicators using self-reported water consumption weighted by arsenic measured in drinking water sources. There were no overall confounder-adjusted effects for arsenic exposure on birth outcomes. Yet, higher average arsenic (10μg/L) was associated with a −2.45 lower birth weight Z-score (P=0.021) and a −1.17 shorter birth length Z-score (P=0.029) among smokers. Higher average iAs (10μg/L) was also associated with smaller ponderal index in boys (P=0.023). Our results suggest smoking may potentiate an otherwise benign arsenic exposure. A larger, more definitive biomarker-based study is needed to investigate the potential risks in conjunction with smoking.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to ...immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Kras
; Trp53
; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-
/
-
/Trp53
) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti-PD-1 therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
High level arsenic exposure is associated with reproductive toxicity in experimental and observational studies; however, few data exist to assess risks at low levels. Even less data are available to ...evaluate the impact of low level arsenic exposure on human fecundity. Our aim in this pilot study was a preliminary evaluation of associations between low level drinking water arsenic contamination and female fecundity. This retrospective study was conducted among women previously recruited to a hospital-based case-control study of spontaneous pregnancy loss in Timiṣ County, Romania. Women (n=94) with planned pregnancies of 5–20 weeks gestation completed a comprehensive physician-administered study questionnaire and reported the number of menstrual cycles attempting to conceive as the time to pregnancy (TTP). Drinking water samples were collected from residential drinking water sources and we determined arsenic levels using hydride generation-atomic absorption spectrometry (HG-AAS). Multivariable Cox-proportional hazards regression with Efron approximation was employed to evaluate TTP as a function of drinking water arsenic concentrations among planned pregnancies, adjusted for covariates. There was no main effect for drinking water arsenic exposure, yet the conditional probability for pregnancy was modestly lower among arsenic exposed women with longer TTPs, relative to women with shorter TTPs, and relative to unexposed women. For example, 1µg/L average drinking water arsenic conferred 5%, 8%, and 10% lower likelihoods for pregnancy in the 6th, 9th, and 12th cycles, respectively (P=0.01). While preliminary, our results suggest that low level arsenic contamination in residential drinking water sources may further impair fecundity among women with longer waiting times; however, this hypothesis requires confirmation by a future, more definitive study.
•We assessed low level drinking water arsenic as a predictor of fecundability.•Arsenic did not affect time to pregnancy among women conceiving quickly.•Arsenic increased time to pregnancy among women taking longer to conceive.•Low level drinking water arsenic may adversely impact women with lower fecundity.
•Positive and negative emotions are related to maintenance or decline of health.•Mixed emotions, reflecting one’s ability to regulate emotions, impact health.•Emotion regulation, a transdiagnostic ...process, also influences physical health.•Emotions affect health by altering biological function and health-related behaviors.•Emotions influence biological processes like inflammation and metabolic profiles.
Both positive (e.g., happiness) and negative (e.g., anxiety) emotions have been distinctively associated with health and disease outcomes. However, whether emotion-related effects are driven by specific emotions or by shared underlying features of similar co-occurring (or mixes of) emotions is still debated. This narrative review summarizes recent scientific advances regarding whether mixed emotions and emotion regulation abilities influence physical health over the lifecourse. While behavioral and biological pathways are commonly proposed to explain these relationships, biological pathways are less well understood. As a result, here we specifically focus on known and novel biological pathways. Future directions for empirical and clinical research aimed at identifying ways to lower the risk of and burden related to chronic diseases are also discussed.
To examine women’s emotional responses to learning the diagnosis of premature ovarian failure (POF) and identify the sources of support used for coping.
Observational study.
National Institutes of ...Health Clinical Center.
One hundred women previously diagnosed with POF of median age 28 years at diagnosis.
Structured telephone interviews based on focus group findings.
Manner informed of POF diagnosis, emotional response, and areas of emotional support.
Overall, 71% were unsatisfied with the manner in which they were informed by their clinician, and 89% reported experiencing moderate to severe emotional distress at the time. The degree of emotional distress was positively correlated with the degree of dissatisfaction with the manner in which the women had been informed of the diagnosis. Thorough and accurate medical information on POF, support of others, and spirituality were perceived as helpful in coping.
Learning the diagnosis of POF can be emotionally traumatic and difficult for women. The findings suggest that the manner in which patients are informed of this diagnosis can significantly impact their level of distress. Patients perceive a need for clinicians to spend more time with them and provide more information about POF.
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