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Burn excision has emerged as the dominant clinical paradigm in treatment of deep burns. Surgical intervention is common but the timing of wound excision is a balance between wound depth assessment, avoidance of infection and unnecessary intervention. However the physiological impact of timing of excision and consequences for the immune response are not well understood.Mice were subject to full-thickness burn (8% TBSA) followed by early (day 1) or late (day 8) surgical excision. Draining lymph nodes, wound tissue and sera were collected longitudinally at day 2 and day 6 after excision and analyzed for cytokine, dendritic cell and T cell profiles using FACS and multiplex ELISA assays.Delayed excision after injury initiated acute and severe inflammatory responses, with high levels of inflammatory cytokines, increased chemokine responses, and elevated Th2 promoting cytokines compared to early excision. Cellular inflammation in the wound was exacerbated with elevated neutrophils, eosinophil and monocytes. Wound cellular innate immune response decreased after late excision with a loss of inflammatory dendritic cells (DC), decreased NKT cells, and inhibition of NK cell activation. Systemically late excision increased trafficking conventional CD8α(-) DC to the lymph node, but there was no apparent DC activation. This was reflected in the induction of CD4T regulatory (Treg) cells and suppression of CD8T cell proliferation after late excision. No suppression was observed with early excision.This data suggests early excision of the wound, during the phase of immune down-regulation initiated by the burn, maintains an innate and adaptive immune cell response. In contrast, late wound excision induced a severe inflammatory response, with subsequent down-regulation of innate and adaptive immune cell responses. Therefore timing of excision is critical in affecting the immune response to burn.

Background Recent population studies have shown an increase in cancer rates in patients after burn injury over a 30-year follow-up period. This work aims to understand the mediators and mechanisms that lead to cancer susceptibility after acute burn. Methods In silico analytics with Watson for Drug Discovery were performed to interrogate networks and pathways in common between burn injury and cancer to better understand the possible mechanistic links. We then useda murine non-severe burn injury model (injury to ∼ 6% body surface area) with subsequent tumor susceptibility evaluation using B16 melanoma challenge 4 weeks after the burn injury. Primary tumor growth (n = 10) and metastasis (n = 11-13) were assessed compared to sham controls. Results Network analysis highlighted multiple overlapping pathways important in burn repair and in tumors. In particular, the evidence suggested links to pathways important in the immune response to burn injury (including well characterized pro-inflammatory genes such as IL-6 and TNF-α) and matrix remodeling (such as MMP9) to metastasis. In the murine model, at four weeks after burn injury, primary tumor growth was unaffected (mean volume 353.7mm3± 235.4 vs 256.8mm3± 122.6, burn injury and control respectively, p = 0.32). However, mean number of metastases in burn injury mice was significantly increased (7.7± 4.1 compared with 2.6 ± 1.8 for control mice (p = 0.0015)), and there was a trend for increased metastatic tumor volume (mean volume 2.7 ± 1.2 compared with 1.6 ±1.3 cm3 respectively, p = 0.08) after burn injury. Conclusions This work suggests burn injury increases cancer susceptibility, specifically through increased number and size of metastases. Further work to delineate the mechanism, potentially through modulation of in silico-identified immune system and metastasis pathways, may provide potential to improve long-term health outcomes for patients. Legal entity responsible for the study Fiona Woods Institute. Funding IBM Watson Health. Disclosure All authors have declared no conflicts of interest.

Rapamycin is an immunosuppressive agent routinely used in organ transplantation but also paradoxically exerts antiviral and antitumor activities. Pathogen-specific memory CD8(+) T-cell (T(CD8) ) responses were recently found to be augmented by rapamycin. However, whether rapamycin influences the magnitude and quality of anticancer T(CD8) responses is unknown. Importantly, how rapamycin may regulate simultaneous virus/tumor-specific and alloreactive T(CD8) in the same host remains unexplored. To answer these questions, we primed wild-type mice with allogeneic cells concomitantly expressing simian virus 40 large tumor antigen (T Ag), a viral oncoprotein with well-defined epitopes. Rapamycin selectively enhanced the cross-priming of T(CD8) specific for T Ag's most immunodominant epitope called site IV but not T(CD8) alloreactivity. Rapamycin-treated mice also had a high percentage of splenic CD127(high) KLRG1(low) T(CD8) and an increased frequency of site IV-specific T cells long after the peak of their primary response. When site IV was presented as a cytosolic minigene encoded by a recombinant vaccinia virus, rapamycin failed to boost the site IV-specific response. Therefore, the nature and presentation mode of antigen determine the susceptibility to the adjuvant effect of rapamycin. Our findings reveal the unexpected benefit of rapamycin treatment in recipients of allografts co-expressing tumor/viral Ags.

SummarySkin dendritic cells (DCs) are thought to act as key initiators of local T cell immunity. Here we show that after skin infection with herpes simplex virus (HSV), cytotoxic T lymphocyte (CTL) activation required MHC class I-restricted presentation by nonmigratory CD8+ DCs rather than skin-derived DCs. Despite a lack of direct presentation by migratory DCs, blocking their egress from infected skin substantially inhibited class I-restricted presentation and HSV-specific CTL responses. These results support the argument for initial transport of antigen by migrating DCs, followed by its transfer to the lymphoid-resident DCs for presentation and CTL priming. Given that relatively robust CTL responses were seen with small numbers of skin-emigrant DCs, we propose that this inter-DC antigen transfer functions to amplify presentation across a larger network of lymphoid-resident DCs for efficient T cell activation.