Patient-Important Needs and Goals Related to Nutrition Interventions during Cancer Treatment.

Patients with cancer often experience nutrition-related challenges for which they are subsequently connected with nutritional support. Yet to date there are no validated tools to assess whether nutrition interventions sufficiently address patients' needs. A vital step toward developing a tool is to identify primary patient-important goals related to receiving nutrition support during cancer care. To that end, we interviewed patients and clinicians to identify nutrition-related needs and goals of patients undergoing cancer treatment. We interviewed 31 patients undergoing cancer treatment and 17 clinicians at the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, PA. Two coders analyzed transcripts using a conventional qualitative content analysis approach. Patients and clinicians both identified weight maintenance, improved food satisfaction and intake, and improved quality of life metrics - such as reduced emotional and financial stress - as top nutrition-related goals. Participants also highlighted the importance of patients receiving food they like and having control over what they eat when designing optimal nutrition interventions. These findings will be used in future work to create a patient-centered assessment tool designed to capture a range of patient goals related to nutrition interventions.

Implementation and Outcomes of the Trauma Ambassadors Program: A Case Study of Trauma-Informed Youth Leadership Development.

Community-based programs serve a critical need for vulnerable youth and families. In recent years, researchers and practitioners have urged programs to adopt a trauma-informed care (TIC) approach to address adversity in young people's lives. The purpose of this article is to describe the implementation and outcomes of the Trauma Ambassador (TA) Program, a pilot youth leadership program guided by a community-university partnership that utilized a TIC approach in an underserved East North Philadelphia neighborhood. Fourteen youth engaged in interactive trainings to build their understanding of trauma and develop practical tools to support encounters with individuals with trauma histories. Focus groups and individual interviews were conducted to better understand program implementation and outcomes. Rich data emerged that identifies a myriad of ways that youth and their community might benefit from a program like the one described. The program successfully impacted participants, as TAs recognized their own trauma and were motivated to help others who may have trauma histories. This program provided quality youth development experiences, particularly with respect to trauma-informed care, and results support taking a holistic, healing-centered approach to foster well-being for youth and adult mentors.

Perspectives of COVID-19 vaccine-hesitant emergency department patients to inform messaging platforms to promote vaccine uptake.

OBJECTIVES: Efforts to promote COVID-19 vaccine acceptance must consider the critical role of the emergency department (ED) in providing health care to underserved patients. Focusing on patients who lacked primary care, we sought to elicit the perspectives of unvaccinated ED patients regarding COVID-19 vaccination concerns and potential approaches that might increase their vaccine acceptance. METHODS: We conducted this qualitative interview study from August to November 2021 at four urban EDs in San Francisco, California; Seattle, Washington; Durham, North Carolina; and Philadelphia, Pennsylvania. We included ED patients who were ≥18 years old, fluent in English or Spanish, had not received a COVID-19 vaccine, and did not have primary care physicians or clinics. We excluded patients who were unable to complete an interview, in police custody, under suspicion of active COVID-19 illness, or presented with a psychiatric chief complaint. We enrolled until we reached thematic saturation in relevant domains. We analyzed interview transcripts with a content analysis approach focused on identifying concerns about COVID-19 vaccines and ideas regarding the promotion of vaccine acceptance and potential trusted messengers. RESULTS: Of 65 patients enrolled, 28 (43%) identified as female, their median age was 36 years (interquartile range 29-49), and 12 (18%) interviews were conducted in Spanish. Primary concerns about COVID-19 vaccines included risk of complications, known and unknown side effects, and fear of contracting COVID-19 from vaccines. Trust played a major role for patients in deciding which sources to use for vaccine information and in engendering vaccine acceptance. Health care providers and family or friends were commonly cited as trusted messengers of information. CONCLUSIONS: We characterized concerns about COVID-19 vaccines, uncovered themes that may promote vaccine acceptance, and identified trusted messengers-primarily health care professionals. These data may inform the development of nuanced COVID-19 vaccine messaging platforms to address COVID-19 vaccine hesitancy among underserved ED populations.

A Prioritized Patient-Centered Research Agenda to Reduce Disparities in Telehealth Uptake: Results from a National Consensus Conference.

Introduction: We hosted a national consensus conference with a diverse group of stakeholders to develop a patient-centered research agenda focused on reducing disparities in telehealth use. Methods: Attendees were purposively invited to participate in a 2-day virtual conference. The group developed a prioritized research agenda focused on reducing disparities in telehealth uptake, with discussion informed by findings from a scoping review. All work was conducted in partnership with a Steering Committee of national experts in telehealth and patient-centered care (n = 5) and a community-based Telehealth Advisory Board with experience with telehealth use and barriers (n = 8). Results: Sixty individuals participated in the conference and discussion resulted in a final list of 20 questions. Fifty-two attendees voted on the final prioritization of these questions. Results were aggregated for all voters (n = 52) and patient-only voters (n = 8). The top question identified by both groups focused on patient and family perspectives on important barriers to telehealth use. The entire group voting identified telehealth's impact on patient outcomes as the next most important questions, while the patient-only group identified trust-related considerations and cultural factors impacting telehealth use as next priorities. Conclusions: This project involved extensive patient and stakeholder engagement. While voting varied between patients only and the entire group of conference attendees, top identified priorities included patient and family perspectives on important barriers to telehealth, trust and cultural barriers and facilitators to telehealth, and assessment of telehealth's impact on patient outcomes. This research agenda can inform design of future research focused on addressing disparities in telehealth use.

"If I had them, I would use them every time": Perspectives on fentanyl test strip use from people who use drugs.

INTRODUCTION: Fentanyl contamination in the illicit drug supply has contributed to a significant increase in overdose deaths in the United States. Fentanyl test strips (FTS), which can detect the presence of fentanyl in drugs, are increasingly given to people who use drugs (PWUD) as an overdose prevention intervention. No studies to date have described PWUD's perspectives from a real-world setting about ideal FTS program characteristics. These perspectives, specifically any identified facilitators, barriers, and suggestions for use, are crucial to informing scalability and implementation of FTS. METHODS: The study team conducted qualitative interviews between January and May 2021 with PWUD in Philadelphia, PA, who had used FTS on a variety of substances. The study recruited participants outside of a harm reduction agency and provided informed consent. The team conducted interviews utilizing a semi-structured interview guide, and audio-recorded and transcribed them. The research team analyzed interviews with a conventional content analysis approach. RESULTS: A total of 29 PWUD participated in an interview. Participants were predominantly cisgender male (n = 21, 72.4%) and White (n = 18, 62.1%). Participants reported previously using FTS on heroin (65.5%), crack cocaine (55.2%), powder cocaine (48.3%), synthetic cannabinoids (31.0%), and benzodiazepines (24.1%). Eighty-six percent of participants learned about FTS through harm reduction or other social service organizations. Most participants incorporated FTS into their daily lives and found them easy to use. Participants identified key barriers, including lack of necessary supplies needed to test, not having an ideal testing location, and confusion reading test results. Suggestions included adding supplies needed for using FTS to distribution packets, ensuring that each PWUD receives enough FTS per distribution, and expanding the types of programs distributing FTS. CONCLUSIONS: While most participants reported FTS as practical and easy to use, participants identified a few key barriers to use that should be addressed to optimize FTS use across a broader population. These barriers include expanding training materials and distributing additional testing materials (e.g., water, cookers) with FTS. Findings can inform sustainable and effective FTS distribution practices, such as distributing FTS in packs of 20 and distributing at other locations that regularly interact with PWUD (e.g., emergency departments, housing shelters, and food banks).

Simple and economical HandClench Relaxometer device for reliable and sensitive measurement of grip myotonia in myotonic dystrophy.

Grip myotonia and weakness are attractive treatment response biomarkers in clinical trials of myotonic dystrophy type 1 (DM1). There is a need to develop simple, patient-friendly and reproducible methods of quantifying grip myotonia in multisite trial settings. We designed a HandClench Relaxometer (HCR) that measures grip myotonia and strength. In contrast with the existing quantitative myometry (QMA) setup, the HCR is portable, economical, can be used with any laptop and generates automated command prompts. We demonstrate the feasibility and reliability of HCR device in twenty DM1 individuals and ten age-matched controls; patients returned for follow up within two months. The device showed excellent day to day reproducibility (ICC >0.80) in patients. The HCR device detected myotonia in milder muscle disease and measured longer myotonia duration than QMA indicating enhanced sensitivity for quantifying myotonia in DM1. The reaction time to the relax but not squeeze command was delayed and showed warm up similar to myotonia in DM1. HCR outcomes were correlated with key pinch strength, hand dexterity test, and fat replacement in the MRI of the long finger flexor muscles. Use of the HCR is warranted for grip myotonia and strength measurements in longitudinal observational and interventional studies of DM1.

"You can't go wrong being safe": Motivations, patterns, and context surrounding use of fentanyl test strips for heroin and other drugs.

BACKGROUND: Unintentional drug overdose fatalities due to fentanyl contamination continue to increase. Fentanyl test strip (FTS) use has emerged as a valuable harm reduction strategy to detect the presence of fentanyl in drugs. However, motivation for FTS uptake and context surrounding use have not been well characterized in the literature. This study aimed to capture people who use drugs' (PWUD) lived experiences to understand motivations underlying FTS uptake, ongoing use, and actions after testing. METHODS: We conducted qualitative interviews with PWUD at a harm reduction organization in Philadelphia, PA. Interviews asked about experiences with using FTS. Interviews were audio-recorded, professionally transcribed, and reviewed. Data were analyzed through a conventional content analysis approach and organized into broader categories via team consensus. RESULTS: Twenty-nine PWUD with experience using FTS were interviewed between January and May 2021. Interviews were organized into three thematic categories: first time use of FTS, patterns of FTS use, and contextual factors of FTS use. Motivations to use FTS among PWUD varied, but were largely driven by factors related to knowledge, access, neighborhood, and drug market trends. Frequency of use was characterized by number of FTS, ongoing FTS access, and drug purchasing location and amount. Participants reported few logistical barriers to testing. CONCLUSION: This research supports the current literature that states FTS are an accepted and effective harm reduction strategy for the PWUD community. To support increased use of FTS, distribution campaigns should be widespread geographically and provide enough strips to ensure availability for PWUD to test more frequently.

Perspectives of people in Philadelphia who use fentanyl/heroin adulterated with the animal tranquilizer xylazine; Making a case for xylazine test strips.

Background: Xylazine is an animal tranquilizer increasingly detected in those who have died of an opioid overdose in Philadelphia, PA and elsewhere. Despite an increasing presence of xylazine in the local fentanyl/heroin drug market and its association with ulcers, there are few perspectives about xylazine from people who use drugs and no data about the utility of a hypothetical xylazine test strip. Methods: Between January to May 2021 in Philadelphia, PA, people who used fentanyl/heroin and had previously used fentanyl test strips were queried about xylazine and hypothetical xylazine test strips. Interviews were transcribed and analysis was conducted via conventional content analysis. Results: Participants (7 spontaneously, 6 after probing, n = 13) discussed "tranq" (i.e., xylazine) in the fentanyl/heroin supply. None enjoyed tranq or wanted it in their fentanyl/heroin. Participants suspected xylazine saturation of the fentanyl/heroin market, disliked the sensation of the drug, and had safety concerns about xylazine exposure. Participants did not indicate concerns about overdose. All were interested in hypothetical xylazine test strips. While previous literature indicates that some people enjoy tranq in their fentanyl/heroin, our findings differed, with participants expressing concern about the consequences of undesired exposure. The interest expressed for xylazine test strips by people who use fentanyl/heroin is an important opportunity to center their voices in the development of innovations designed to mitigate the harms of unwanted adulterant exposure. Conclusions: In the present study, people who use fentanyl/heroin indicated an interest to test their drug for the presence of xylazine prior to use.

Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses.

Purpose: Malignant gliomas have a highly immune suppressive tumor microenvironment (TME) which renders them largely unresponsive to conventional therapeutics. Therefore, the present study evaluated a therapeutic protocol designed overcome the immune barrier by combining myeloid cell targeted immunotherapy with tumor vaccination. Experimental Design: We utilized a spontaneously occurring canine glioma model to investigate an oral TME modifying immunotherapy in conjunction with cancer stem cell (CSC) vaccination. Dogs were treated daily with losartan (monocyte migration inhibitor) and propranolol (myeloid-derived suppressor cell depleting agent) plus anti-CSC vaccination on a bi-weekly then monthly schedule. Tumor volume was monitored by MRI and correlated with patient immune responses. Results: Ten dogs with histologically confirmed gliomas were enrolled into a prospective, open-label clinical trial to evaluate the immunotherapy protocol. Partial tumor regression was observed in 2 dogs, while 6 dogs experienced stable disease, for an overall clinical benefit rate of 80%. Overall survival times (median = 351 days) and progression-free intervals (median = 163 days) were comparable to prior studies evaluating surgical debulking followed by immunotherapy. Dogs with detectable anti-CSC antibody responses had an increased overall survival time relative to dogs that did not generate antibody responses (vaccine responder MST = 500 days; vaccine non-responder MST = 218 days; p = 0.02). Conclusions: These findings suggest that combining myeloid cell targeted oral immunotherapy with tumor vaccination can generate objective tumor responses, even in the absence of conventional therapy. Overall, this approach has promise as a readily implemented therapeutic strategy for use in brain cancer patients.

Filling Gaps and Setting Boundaries: Examining Utilization of Health and Social services at JeffHOPE Student Run Clinics.

The objective of this study was to describe the frequency that healthcare and social support services offered by JeffHOPE, a student run clinic for people experiencing homelessness in Philadelphia, PA, were utilized by patients. This study also aimed to investigate where patients would seek medical care on a given day had they not been able to access JeffHOPE. This study was conducted via mixed methods consisting of retrospective chart review of patient encounter records and a patient survey conducted weekly throughout 2019, both at a single clinic site, and retrospective chart review of January through March 2020 records at 5 clinic sites. This study found that the frequency of services utilized varied between clinic sites, and that Pharmacy and Procedure committees were the most utilized when examining the combined clinic data. Additionally, the survey found that JeffHOPE provided medical care to those that otherwise would not have sought it. Clinics also served as an alternative to accessing care for non-emergent issues in an Emergency Department (ED) for some patients, but for others it replaced seeing their primary care provider (PCP). This study confirmed that the services offered by JeffHOPE are well-utilized by patients experiencing homelessness in Philadelphia. It also revealed that while the organization's medical services filled care gaps and potentially decreased unnecessary ED visits, they were also sometimes accessed in lieu of a PCP visit. A focused effort on linkage to formal primary care services for all JeffHOPE patients and expanding collection of more granular data to all clinics represent important future endeavors for this student run organization.

Targeting Fat Oxidation in Mouse Prostate Cancer Decreases Tumor Growth and Stimulates Anti-Cancer Immunity.

Lipid catabolism represents an Achilles heel in prostate cancer (PCa) that can be exploited for therapy. CPT1A regulates the entry of fatty acids into the mitochondria for beta-oxidation and its inhibition has been shown to decrease PCa growth. In this study, we examined the pharmacological blockade of lipid oxidation with ranolazine in TRAMPC1 PCa models. Oral administration of ranolazine (100 mg/Kg for 21 days) resulted in decreased tumor CD8+ T-cells Tim3 content, increased macrophages, and decreased blood myeloid immunosuppressive monocytes. Using multispectral staining, drug treatments increased infiltration of CD8+ T-cells and dendritic cells compared to vehicle. Functional studies with spleen cells of drug-treated tumors co-cultured with TRAMPC1 cells showed increased ex vivo T-cell cytotoxic activity, suggesting an anti-tumoral response. Lastly, a decrease in CD4+ and CD8+ T-cells expressing PD1 was observed when exhausted spleen cells were incubated with TRAMPC1 Cpt1a-KD compared to the control cells. These data indicated that genetically blocking the ability of the tumor cells to oxidize lipid can change the activation status of the neighboring T-cells. This study provides new knowledge of the role of lipid catabolism in the intercommunication of tumor and immune cells, which can be extrapolated to other cancers with high CPT1A expression.

Pilot Acute Safety Evaluation of Innocell™ Cancer Immunotherapy in Canine Subjects.

BACKGROUND: We are developing cancer immunotherapy based on the use of autologous tumor tissue that has been rendered replication-incompetent but maintains phenotype and metabolic activity post-preparation. AIM: The aim of this study was to evaluate safety and tolerance to injection of the inactivated tumor cell and adjuvant preparation (Innocell™) within 24 hours of administration in a pilot study in canine patients with solid organ tumors. Methodology. Three canine patients demonstrating accessible solid organ tumors of various types were assessed in this study. The local site injection was monitored post-treatment. Clinical signs of adverse reactions were monitored for 24 hours post-treatment. Blood samples were taken pre-treatment and at 8 and 24 hours post-treatment for all subjects. One subject provided samples at 7 days post-treatment. All blood samples were analyzed for cytokine content for both immune system-associated and tumor-associated cytokines. RESULTS: No signs of adverse reactions at the site of injection or systemically were observed in the study period. A slight fever and lethargy were reported in one subject by the owner post-vaccination. Immune system-associated cytokine levels in two of the three animals were elevated post-treatment. Tumor-associated cytokine levels in all three subjects declined post-treatment from baseline levels with the effect most prominent in the subject with a non-excised tumor. CONCLUSION: Subcutaneous injection of the inactivated tumor cells and adjuvant was well tolerated in this pilot study. Cytokine responses observed were in line with the intended use of the treatment in stimulating immune response without adverse clinical observations. Additional evaluation is warranted.

An Interdisciplinary Approach to Implementing the Age-Friendly Health System 4Ms in an Ambulatory Clinical Pathway With a Focus on Medication Safety.

MedStar's Center for Successful Aging (CSA) participated in the Age-Friendly Health Systems initiative led by The John A. Hartford Foundation and the Institute for Healthcare Improvement in partnership with the American Hospital Association and the Catholic Health Association of the United States. This initiative focuses on bringing the 4Ms framework-What Matters, Medication, Mentation, and Mobility-to caring for older adults. A quality improvement project was conducted at the CSA to integrate the 4Ms framework into the CSA ambulatory clinical pathway. Our interventions found upward trends in patients receiving 4Ms care during their new patient visits. Positive preliminary feedback was also obtained from providers following the incorporation of the 4Ms framework in the high-risk rounds discussion. A focus on high-risk medications and deprescribing illustrated positive clinical outcomes. This ongoing interprofessional collaboration illustrates the importance of person-centered care and quality improvement to achieve Age-Friendly Health Systems status within an ambulatory practice. [Journal of Gerontological Nursing, 46(10), 7-11.].

A novel cancer immunotherapy utilizing autologous tumour tissue.

BACKGROUND: With the recent interest in personalized medicine for cancer patients and immune therapy, the field of cancer vaccines has been resurrected. Previous autologous, whole cell tumour vaccine trials have not produced convincing results due, in part to poor patient selection and inactivation methos that are harsh on the cells. These methods can alter protein structure and antigenic profiles making vaccine candidates ineffective in stimulating immune response to autochthonous tumour cells. MATERIALS AND METHODS: We investigated a novel method for inactivating tumour cells that uses UVA/UVB light and riboflavin (vitamin B2) (RF + UV). RF + UV inactivates the tumour cells' ability to replicate, yet preserves tumour cell integrity and antigenicity. RESULTS: Our results demonstrate that proteins are preserved on the surface of RF + UV-inactivated tumour cells and that they are immunogenic via induction of dendritic cell maturation, increase in IFNγ production and generation of tumour cell-specific IgG. Moreover, when formulated with an adjuvant ('Innocell vaccine') and tested in different murine tumour primary and metastatic disease models, decreased tumour growth, decreased metastatic disease and prolonged survival were observed. In addition, immune cells obtained from tumour tissue following vaccination had decreased exhausted and regulatory T cells, suggesting that activation of intra-tumoural T cells may be playing a role leading to reduced tumour growth. CONCLUSIONS: These data suggest that the RF + UV inactivation of tumour cells may provide an efficacious method for generating autologous whole tumour cell vaccines for use in cancer patients.

The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment.

Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated primarily via the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b+/Ly6C+-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.

Cancer stem cell populations in lymphoma in dogs and impact of cytotoxic chemotherapy.

Cancer relapse following chemotherapy has been attributed in part to the presence of cancer stem cells (CSC), which drive tumour growth and metastasis and are highly resistant to the effects of cytotoxic chemotherapy. As a result, treatment with cytotoxic chemotherapy selects for drug-resistant CSC populations that eventually drive tumour recurrence. Little is known currently regarding the role of CSC in dogs with lymphoma, nor the impact of chemotherapy on CSC populations. Therefore, we prospectively quantitated CSC populations in dogs with B-cell (BCL) and T-cell lymphoma (TCL), using tumour aspirates and flow cytometric analysis with a panel of CSC markers. In addition, in vitro studies were carried out to determine the impact of chemotherapy resistance on the stem cell phenotype and stem cell properties of lymphoma cells. We found that the percentages of tumour cells expressing CSC markers were significantly increased in dogs with BCL, compared with B cells from normal lymph nodes. Similar findings were observed in dogs with TCL. In vitro studies revealed that lymphoma cells selected for resistance to CHOP chemotherapy had significantly upregulated expression of CSC markers, formed spheroids in culture more readily, and expressed significantly greater aldehyde dehydrogenase activity compared with chemotherapy-sensitive tumour cells. Similar results were observed in tumour samples dogs with relapsed BCL. These findings suggest that cytotoxic chemotherapy can lead to a relative enrichment of tumour cells with CSC properties, which may be associated with lymphoma recurrence.

Mesenchymal Stem Cells Recruit CCR2+ Monocytes To Suppress Allergic Airway Inflammation.

Mesenchymal stem cells (MSC) exert immune modulatory properties and previous studies demonstrated suppressive effects of MSC treatment in animal models of allergic airway inflammation. However, the underlying mechanisms have not been fully elucidated. We studied the role of MSC in immune activation and subsequent recruitment of monocytes in suppressing airway hyperresponsiveness and airway inflammation using a mouse model of allergic airway inflammation. MSC administration prior to or after allergen challenge inhibited the development of airway inflammation in allergen-sensitized mice. This was accompanied by an influx of CCR2-positive monocytes, which were localized around injected MSC in the lungs. Notably, IL-10-producing monocytes and/or macrophages were also increased in the lungs. Systemic administration of liposomal clodronate or a CCR2 antagonist significantly prevented the suppressive effects of MSC. Activation of MSC by IFN-γ leading to the upregulation of CCL2 expression was essential for the suppressive effects, as administration of wild-type MSC into IFN-γ-deficient recipients, or IFN-γ receptor-deficient or CCL2-deficient MSC into wild-type mice failed to suppress airway inflammation. These results suggest that MSC activation by IFN-γ, followed by increased expression of CCL2 and recruitment of monocytes to the lungs, is essential for suppression by MSC in allergen-induced airway hyperresponsiveness and airway inflammation.

Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α.

PD-L1 is an immune checkpoint protein that has emerged as a major signaling molecule involved with tumor escape from T cell immune responses. Studies have shown that intra-tumoral expression of PD-L1 can inhibit antitumor immune responses. However, it has recently been shown that expression of PD-L1 on myeloid cells from the tumor is a stronger indicator of prognosis than tumor cell PD-L1 expression. Therefore, it is important to understand the factors that govern the regulation of PD-L1 expression on tumor-infiltrating myeloid cells. We found that immature bone marrow monocytes in tumor-bearing mice had low levels of PD-L1 expression, while higher levels of expression were observed on monocytes in circulation. In contrast, macrophages found in tumor tissues expressed much higher levels of PD-L1 than circulating monocytes, implying upregulation by the tumor microenvironment. We demonstrated that tumor-conditioned media strongly induced increased PD-L1 expression by bone marrow-derived monocytes and TNF-α to be a cytokine that causes an upregulation of PD-L1 expression by the monocytes. Furthermore, we found production of TNF-α by the monocytes themselves to be a TLR2-dependent response to versican secreted by tumor cells. Thus, PD-L1 expression by tumor macrophages appears to be regulated in a different manner than by tumor cells themselves.

Cancer immunotherapy in veterinary medicine: Current options and new developments.

Excitement in the field of tumor immunotherapy is being driven by several remarkable breakthroughs in recent years. This review will cover recent advances in cancer immunotherapy, including the use of T cell checkpoint inhibitors, engineered T cells, cancer vaccines, and anti-B cell and T cell antibodies. Inhibition of T cell checkpoint molecules such as PD-1 and CTLA-4 using monoclonal antibodies has achieved notable success against advanced tumors in humans, including melanoma, renal cell carcinoma, and non-small cell lung cancer. Therapy with engineered T cells has also demonstrated remarkable tumor control and regression in human trials. Autologous cancer vaccines have recently demonstrated impressive prolongation of disease-free intervals and survival times in dogs with lymphoma. In addition, caninized monoclonal antibodies targeting CD20 and CD52 just recently received either full (CD20) or conditional (CD52) licensing by the United States Department of Agriculture for clinical use in the treatment of canine B-cell and T-cell lymphomas, respectively. Thus, immunotherapy for cancer is rapidly moving to the forefront of cancer treatment options in veterinary medicine as well as human medicine.

Comparison of cancer stem cell antigen expression by tumor cell lines and by tumor biopsies from dogs with melanoma and osteosarcoma.

Cancer stem cells (CSCs) represent a small subpopulation of tumor cells that play a critical role in initiating and sustaining tumor growth. However, we currently have an incomplete understanding of the expression patterns of CSC antigens in tumors of dogs, nor do we understand how expression of these antigens vary between tumor cell lines and tumor biopsy specimens. Therefore, we used flow cytometry and commonly reported CSC surface and intracellular markers to evaluate the phenotype and overall frequency of CSC subpopulations in tumor cell lines and primary tumor biopsy samples from dogs with melanoma and osteosarcoma. We found that cells expressing common CSC antigens were rare in tumor cell lines, with the exception of tumor cells expressing CD44 and CD90. In contrast, tumor cells expressing conventional CSC antigens such as CD133, CD34, CD44, CD24 and Oct3/4 were much more common in tumor biopsy samples. Notably, the frequency and types of putative CSC subpopulations were very similar in biopsy samples from dogs with either melanoma or osteosarcoma. Our results suggest that the tumor microenvironment significantly influences CSC subpopulations within tumors and that tumor cell lines may not accurately reflect the actual frequency or types of CSC subpopulations present in tumor tissues in vivo.