While treatment for burn injury has improved significantly over the past few decades, reducing mortality and improving patient outcomes, recent evidence has revealed that burn injury is associated with a number of secondary pathologies, many of which arise long after the initial injury has healed. Population studies have linked burn injury with increased risk of cancer, cardiovascular disease, nervous system disorders, diabetes, musculoskeletal disorders, gastrointestinal disease, infections, anxiety and depression. The wide range of secondary pathologies indicates that burn can cause sustained disruption of homeostasis, presenting new challenges for post-burn care. Understanding burn injury as a chronic disease will improve patient care, providing evidence for better long-term support and monitoring of patients. Through focused research into the mechanisms underpinning long-term dysfunction, a better understanding of burn injury pathology may help with the development of preventative treatments to improve long-term health outcomes. The review will outline evidence of long-term health effects, possible mechanisms linking burn injury to long-term health and current research into burns as a chronic disease.

The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C⁺/CD11b⁺ inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.

Surgical resection of cancer remains the frontline therapy for millions of patients annually, but post-operative recurrence is common, with a relapse rate of around 45% for non-small cell lung cancer. The tumour draining lymph nodes (dLN) are resected at the time of surgery for staging purposes, and this cannot be a null event for patient survival and future response to immune checkpoint blockade treatment. This project investigates cancer surgery, lymphadenectomy, onset of metastatic disease, and response to immunotherapy in a novel model that closely reflects the clinical setting. In a murine metastatic lung cancer model, primary subcutaneous tumours were resected with associated dLNs remaining intact, completely resected or partially resected. Median survival after surgery was significantly shorter with complete dLN resection at the time of surgery (49 days (95%CI)) compared to when lymph nodes remained intact (> 88 days; p < 0.05). Survival was partially restored with incomplete lymph node resection and CD8 T cell dependent. Treatment with aCTLA4 whilst effective against the primary tumour was ineffective for metastatic lung disease. Conversely, aPD-1/aCD40 treatment was effective in both the primary and metastatic disease settings and restored the detrimental effects of complete dLN resection on survival. In this pre-clinical lung metastatic disease model that closely reflects the clinical setting, we observe decreased frequency of survival after complete lymphadenectomy, which was ameliorated with partial lymph node removal or with early administration of aPD-1/aCD40 therapy. These findings have direct relevance to surgical lymph node resection and adjuvant immunotherapy in lung cancer, and perhaps other cancer, patients.

Lung cancer remains the leading cause of cancer‐related death worldwide. The disease is classified into two major subtypes, small‐cell lung cancer (SCLC) and the more prevalent non‐small‐cell lung cancer (NSCLC). First‐line conventional therapies, such as chemotherapy, radiotherapy and surgery, have offered limited benefit, and patient prognosis remains poor with post‐treatment recurrences representing a major cause of morbidity. Consequently, there is an urgent need for improved therapeutic options. Historically, NSCLC has been considered a non‐immunogenic disease. However, increased understanding of tumor‐immune interactions has challenged this paradigm in both lung and other malignancies, with cancer elimination by tumor‐specific T cells increasingly well described in a myriad of solid tumors. Recent evidence has demonstrated that absent or weak anticancer responses are likely a product of tumor‐derived immunosuppression. This knowledge, along with a greater appreciation for the role of T cells in lung cancer elimination, has driven development of novel immunotherapeutic approaches which are demonstrating remarkable clinical efficacy. This review examines the role of T cells in lung cancer, discussing the direction and clinical significance of current and future immunotherapeutic strategies.

Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the best therapeutic option for mesothelioma have yet to be fully elucidated. Here, we used our well characterised mesothelioma tumour model to investigate the efficacy of different ICBP treatments to generate effective therapy for mesothelioma. We show that tumour resident regulatory T cell co-express high levels of CTLA-4, OX40 and GITR relative to T effector subsets and that these receptors are co-expressed on a large proportion of cells. Targeting any of CTLA-4, OX40 or GITR individually generated effective responses against mesothelioma. Furthermore, the combination of αCTLA-4 and αOX40 was synergistic, with an increase in complete tumour regressions from 20% to 80%. Other combinations did not synergise to enhance treatment outcomes. Finally, an early pattern in T cell response was predictive of response, with activation status and ICP receptor expression profile of T effector cells harvested from tumour and dLN correlating with response to immunotherapy. Taken together, these data demonstrate that combination ICPB can work synergistically to induce strong, durable immunity against mesothelioma in an animal model.