OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification.

PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours.

PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts.

Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy.

Despite tremendous advances in radiotherapy techniques, allowing dose escalation to tumour tissues and sparing of organs at risk, cure rates from radiotherapy or chemoradiotherapy remain suboptimal for most cancers. In tandem with our growing understanding of tumour biology, we are beginning to appreciate that targeting the molecular response to radiation-induced DNA damage holds great promise for selective tumour radiosensitisation. In particular, approaches that inhibit cell cycle checkpoint controls offer a means of exploiting molecular differences between tumour and normal cells, thereby inducing so-called cancer-specific synthetic lethality. In this overview, we discuss cellular responses to radiation-induced damage and discuss the potential of using G2/M cell cycle checkpoint inhibitors as a means of enhancing tumour control rates.

Mouse model for thoracic congenital scoliosis.

SUMMARY: This study sought to produce a dose-response curve for acute and chronic maternal carbon monoxide (CO) exposure versus vertebral anomalies in mouse offspring and to determine the critical day of exposure. In Part I, pregnant CD-1 mice were exposed to an acute dose of CO at 9 days of gestation. A positive dose-response relationship of acute maternal CO exposure and vertebral anomalies in the offspring was produced. In Part II, pregnant females were exposed to chronic CO for the first 11 days of gestation. Chronic exposure to CO did not produce significant vertebral anomalies. In Part III, pregnant females were exposed to an acute dose of 600 ppm of CO at gestation day 8, 9, or 10. Day 9 in this mouse breed is the critical day for maternal exposure to CO. The detected anomalies were predominately in the thoracic spine.