Circulating tumor DNA (ctDNA) is a subset of circulating cell-free DNA released by lysed tumor cells that can be characterized by its shorter strand length and tumor genome-specific information. The relatively short half-life of ctDNA allows it to provide a real-time measure of tumor burden which has potential prognostic and surveillance value as a tumor biomarker. Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer that requires close monitoring due to the high risk of relapse. There are currently no good tumor biomarkers for MCC patients, especially those who are negative for Merkel cell polyomavirus. ctDNA shows promise for improving the prognoses of MCC patients by monitoring tumor burden, identifying minimal residual disease (MRD), and stratifying patients by their likelihood of response to immune checkpoint inhibition or risk of relapse. In particular, bespoke ultra-sequencing platforms allow for the creation of patient-specific mutation panels that improve ctDNA detection, especially for patients with rare or uncharacteristic mutations. Leveraging bespoke ctDNA assays may improve physicians' ability to alter treatment plans for non-responsive or high-risk patients. In addition, ctDNA MRD monitoring may allow physicians to treat relapses early before clinically evident disease is present.

Research Question: The goal of this study is to assess the impact of a required, quarter-long preparatory course on medical students’ ability to effectively participate in a student-run free clinic and grapple with its ethical nuances. Methods: A one-time, cross-sectional survey was administered to all 55 students in the UCSD Student-Run Free Clinic Project’s (SRFCP) quarter-long introductory course. A Linkert 5-point scale was used to survey student’s impressions of how the course impacted 1) clinical skills, 2) understanding of ethics, 3) social and community issues, 4) sense of community, and 5) future motivation to work with the underserved. Mean scores (with standard deviations) were generated for each topic. Results: Students found the course useful for building a variety of clinical skills (3.97), including newly designed sessions such as working with interpreters (4.18) or effectively pre-charting (3.95). The course also deepened students’ awareness of social issues (4.08) and connectedness to peers (3.76), particularly through an MS1-MS4 teaching model (4.38). Students had mixed perceptions (3.55) on the ethical nuances of SRFCP. A majority felt prepared to work with SRFCP (4.16) and underserved groups (4.29) in the future. Significance: This required didactic helped students feel more prepared to work in SRFCP and strengthened long-term motivation to work with the underserved. A breadth of discussion on ethics, community resources, and health equity helped students define their role in an imperfect system. This study is a call to thoughtfully prepare students to work in free clinics in order to provide the highest quality patient care.

Infiltration of regulatory T (Treg) cells, an immunosuppressive population of CD4+ T cells, into solid cancers represents a barrier to cancer immunotherapy. Chemokine receptors are critical for Treg cell recruitment and cell-cell interactions in inflamed tissues, including cancer, and thus are an ideal therapeutic target. Here, we show in multiple cancer models that CXCR3+ Treg cells were increased in tumors compared with lymphoid tissues, exhibited an activated phenotype, and interacted preferentially with CXCL9-producing BATF3+ dendritic cells (DCs). Genetic ablation of CXCR3 in Treg cells disrupted DC1-Treg cell interactions and concomitantly increased DC-CD8+ T cell interactions. Mechanistically, CXCR3 ablation in Treg cells increased tumor antigen-specific cross-presentation by DC1s, increasing CD8+ T cell priming and reactivation in tumors. This ultimately impaired tumor progression, especially in combination with anti-PD-1 checkpoint blockade immunotherapy. Overall, CXCR3 is shown to be a critical chemokine receptor for Treg cell accumulation and immune suppression in tumors.