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1.
Teach Learn Med ; 34(5): 504-513, 2022.
Article in English | MEDLINE | ID: mdl-34763586

ABSTRACT

PROBLEM: 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. INTERVENTION: 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. CONTEXT: 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. IMPACT: 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. LESSONS LEARNED: 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.


Subject(s)
Students, Medical , Male , Female , Humans , Peer Group , Schools, Medical , Social Isolation , Trust
2.
J Immunother Cancer ; 9(11)2021 11.
Article in English | MEDLINE | ID: mdl-34737215

ABSTRACT

BACKGROUND: Pancreatic 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. METHODS: We 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. RESULTS: In 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. CONCLUSIONS: These 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.


Subject(s)
Adenocarcinoma/genetics , Carcinoma, Pancreatic Ductal/genetics , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Immunotherapy/methods , Killer Cells, Natural/metabolism , Receptors, CXCR3/metabolism , T-Lymphocytes/metabolism , Adenocarcinoma/pathology , Animals , CD8-Positive T-Lymphocytes , Carcinoma, Pancreatic Ductal/pathology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Disease Models, Animal , Humans , Mice , Tumor Microenvironment
3.
Genome Med ; 13(1): 129, 2021 08 11.
Article in English | MEDLINE | ID: mdl-34376232

ABSTRACT

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.


Subject(s)
CTLA-4 Antigen/antagonists & inhibitors , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Lymphocyte Activation/genetics , Models, Biological , Neoplasms/genetics , Transcriptome , Animals , Biomarkers , Cell Line, Tumor , Computational Biology/methods , Databases, Genetic , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Ipilimumab/pharmacology , Ipilimumab/therapeutic use , Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mice , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Prognosis , ROC Curve , Treatment Outcome
4.
Cancer Immunol Res ; 9(4): 386-400, 2021 04.
Article in English | MEDLINE | ID: mdl-33509790

ABSTRACT

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+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53 flox/flox ) 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.


Subject(s)
Carcinoma, Pancreatic Ductal/drug therapy , Disease Models, Animal , Nitriles/pharmacology , Pancreatic Neoplasms/drug therapy , Pyrazoles/pharmacology , Pyrimidines/pharmacology , T-Lymphocytes/immunology , Animals , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor/transplantation , Humans , Metallothionein 3 , Mice , Mice, Inbred C57BL , Mice, SCID , Pancreas/immunology , Pancreas/pathology , Pancreatic Neoplasms/pathology , Signal Transduction/drug effects , T-Lymphocytes/drug effects , Tumor Microenvironment , Ubiquitin-Protein Ligases
5.
Cancers (Basel) ; 13(1)2020 Dec 28.
Article in English | MEDLINE | ID: mdl-33379189

ABSTRACT

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.

6.
Cancer Metastasis Rev ; 39(3): 783-803, 2020 09.
Article in English | MEDLINE | ID: mdl-32601975

ABSTRACT

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.


Subject(s)
Gelatinases/metabolism , Membrane Proteins/metabolism , Neoplasms/metabolism , Serine Endopeptidases/metabolism , Animals , Endopeptidases , Gelatinases/chemistry , Gelatinases/genetics , Humans , Membrane Proteins/chemistry , Membrane Proteins/genetics , Models, Molecular , Neoplasms/genetics , Neoplasms/pathology , Serine Endopeptidases/chemistry , Serine Endopeptidases/genetics , Structure-Activity Relationship
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