VEXAS Syndrome-Diagnostic Clues for the Dermatologist and Gaps in Our Current Understanding: A Narrative Review.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome is a newly recognized, acquired autoinflammatory disorder with broad systemic implications and a poor global prognosis. Because cutaneous lesions are present in the majority of those affected, it is necessary that dermatologists are equipped to recognize this important disease. Through identification, there is a greater opportunity for disease stratification, surveillance for systemic involvement, and selection of the best available therapies. As our understanding of this disease develops, dermatologists should also play a role in addressing the knowledge gaps that exist.

Antigen-loaded Monocyte Administration and Flt3 Ligand Augment the Antitumor Efficacy of Immune Checkpoint Blockade in a Murine Melanoma Model.

Undifferentiated monocytes can be loaded with tumor antigens (Ag) and administered intravenously to induce antitumor cytotoxic T lymphocyte (CTL) responses. This vaccination strategy exploits an endogenous Ag cross-presentation pathway, where Ag-loaded monocytes (monocyte vaccines) transfer their Ag to resident splenic dendritic cells (DC), which then stimulate robust CD8 + CTL responses. In this study, we investigated whether monocyte vaccination in combination with CDX-301, a DC-expanding cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), could improve the antitumor efficacy of anti-programmed cell death (anti-PD-1) immune checkpoint blockade. We found that Flt3L expanded splenic DC over 40-fold in vivo and doubled the number of circulating Ag-specific T cells when administered before monocyte vaccination in C57BL/6 mice. In addition, OVA-monocyte vaccination combined with either anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), or anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4) suppressed subcutaneous B16/F10-OVA tumor growth to a greater extent than checkpoint blockade alone. When administered together, OVA-monocyte vaccination improved the antitumor efficacy of Flt3L and anti-PD-1 in terms of circulating Ag-specific CD8 + T cell frequency and inhibition of subcutaneous B16/F10-OVA tumor growth. To our knowledge, this is the first demonstration that a cancer vaccine strategy and Flt3L can improve the antitumor efficacy of anti-PD-1. The findings presented here warrant further study of how monocyte vaccines can improve Flt3L and immune checkpoint blockade as they enter clinical trials.

Antigen-loaded monocyte administration induces potent therapeutic antitumor T cell responses.

Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic CD8+ DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43-containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction-mediated Ag transfer pathway between monocytes and CD8+ DCs and suggest that administration of tumor Ag-loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers.

Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation.

The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein- or ß-arrestin-mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein- and ß-arrestin-mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell-mediated allergic contact hypersensitivity (CHS), topical application of a ß-arrestin-biased, but not a G protein-biased, agonist potentiated inflammation. T cell recruitment was increased by the ß-arrestin-biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and ß-arrestin in T cells. In mouse and human T cells, the ß-arrestin-biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that ß-arrestin-biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.

International Radiotherapy Referrals From Rural Rwanda: Implementation Processes and Early Clinical Outcomes.

PURPOSE: Low- and middle-income countries disproportionately comprise 65% of cancer deaths. Cancer care delivery in resource-limited settings, especially low-income countries in sub-Saharan Africa, is exceedingly complex, requiring multiple modalities of diagnosis and treatment. Given the vast human, technical, and financial resources required, access to radiotherapy remains limited in sub-Saharan Africa. Through 2017, Rwanda has not had in-country radiotherapy services. The aim of this study was to describe the implementation and early outcomes of the radiotherapy referral program at the Butaro Cancer Centre of Excellence and to identify both successful pathways and barriers to care. METHODS: Butaro District Hospital is located in a rural area of the Northern Province and is home to the Butaro Cancer Centre of Excellence. We performed a retrospective study from routinely collected data of all patients with a diagnosis of cervical, head and neck, or rectal cancer between July 2012 and June 2015. RESULTS: Between 2012 and 2015, 580 patients were identified with these diagnoses and were potential candidates for radiation. Two hundred eight (36%) were referred for radiotherapy treatment in Uganda. Of those referred, 160 (77%) had cervical cancer, 31 (15%) had head and neck cancer, and 17 (8%) had rectal cancer. At the time of data collection, 101 radiotherapy patients (49%) were alive and had completed treatment with no evidence of recurrence, 11 (5%) were alive and continuing treatment, and 12 (6%) were alive and had completed treatment with evidence of recurrence. CONCLUSION: This study demonstrates the feasibility of a rural cancer facility to successfully conduct out-of-country radiotherapy referrals with promising early outcomes. The results of this study also highlight the many challenges and lessons learned in providing comprehensive cancer care in resource-limited settings.