Isolation and Characterization of a Novel Mammary Adenocarcinoma, MCa-P1362, with Hormone Receptor Expression, Human Epidermal Growth Factor Receptor 2 Positivity, and Enrichment in Cancer and Mesenchymal Stem Cells.

Preclinical models that display spontaneous metastasis are necessary to improve the therapeutic options for hormone receptor-positive breast cancers. Within this study, detailed cellular and molecular characterization was conducted on MCa-P1362, a newly established mouse model of metastatic breast cancer that is syngeneic in BALB/c mice. MCa-P1362 cancer cells express estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2. MCa-P1362 cancer cells proliferate in vitro and in vivo in response to estrogen, yet do not depend on steroid hormones for growth and tumor progression. Analysis of MCa-P1362 tumor explants revealed the tumors contained a mixture of cancer cells and mesenchymal stromal cells. Through transcriptomic and functional analyses of both cancer and stromal cells, stem cells were detected within both populations. Functional studies demonstrated that MCa-P1362 cancer stem cells drove tumor initiation, whereas stromal cells from these tumors contributed to drug resistance. MCa-P1362 may serve as a useful preclinical model to investigate the cellular and molecular basis of breast tumor progression and therapeutic resistance.

A Multi-Institutional Survey of Radiation Oncology Professionals' Knowledge, Attitudes, and Practice Behaviors Toward Sexual and Gender Minority Patients With Cancer.

Purpose: Sexual and gender minority (SGM) individuals have an increased risk of poor health outcomes, in part due to knowledge and training gaps in health care education. This study sought to evaluate the knowledge, attitudes, and practice behaviors of various health care role groups within radiation oncology toward SGM patients. Methods and Materials: A 38-item web-based survey was emailed to 1045 staff across 2 large radiation oncology departments. The survey assessed demographics, attitudes, knowledge, and practice behaviors. χ2 tests were performed to explore differences in survey responses by age, political affiliation, religious identity, year since graduation, and role groups. One-way analysis of variance tests were conducted to determine differences between respondents' confidence in knowledge and performance on the knowledge section of the survey. Thematic analysis was applied to the open discussion section. Results: Of the 223 respondents, 103 clinicians (physicians/advanced practice providers/nurses) and 120 nonclinicians (administrative staff, medical assistants, and other nonmedical staff) participated in the survey (21.3% response rate): 72.6% answered the knowledge questions; 93.5% stated they were comfortable treating sexual minorities, or lesbian, gay, bisexual, and queer + patients; 88% indicated comfort in treating transgender patients; 36.6% stated they were confident in their knowledge of the health needs of transgender patients; and 50.3% expressed confidence in treating lesbian, gay, bisexual, and queer + patients. Fewer nonclinicians than clinicians thought that gender identity, sexual orientation, and sex assigned at birth were important to provide the best care (P < .05). The open comments section identified key themes, including the belief that current educational tools are not helpful, desire for more educational formats (lectures, case-based learning, seminars), and an overall interest in SGM health education. Conclusions: Most staff feel comfortable in treating SGM patients but are less confident in the distinct needs of this population. Knowledge gaps persist for both clinicians and nonclinicians, indicating a need for further training specific to oncology care.

Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.