Harnessing the cGAS-STING pathway to potentiate radiation therapy: current approaches and future directions.

In this review, we cover the current understanding of how radiation therapy, which uses ionizing radiation to kill cancer cells, mediates an anti-tumor immune response through the cGAS-STING pathway, and how STING agonists might potentiate this. We examine how cGAS-STING signaling mediates the release of inflammatory cytokines in response to nuclear and mitochondrial DNA entering the cytoplasm. The significance of this in the context of cancer is explored, such as in response to cell-damaging therapies and genomic instability.

Cognitive and behavioral effects of whole brain conventional or high dose rate (FLASH) proton irradiation in a neonatal Sprague Dawley rat model.

Recent studies suggest that ultra-high dose rates of proton radiation (>40 Gy/s; FLASH) confer less toxicity to exposed healthy tissue and reduce cognitive decline compared with conventional radiation dose rates (~1 Gy/s), but further preclinical data are required to demonstrate this sparing effect. In this study, postnatal day 11 (P11) rats were treated with whole brain irradiation with protons at a total dose of 0, 5, or 8 Gy, comparing a conventional dose rate of 1 Gy/s vs. a FLASH dose rate of 100 Gy/s.

Extraneural recurrence of an intracranial nongerminomatous germ cell tumor to cervical lymph nodes in a pediatric patient: Case report.

Background: Intracranial germ cell tumors (GCTs) comprise 3%-5% of pediatric primary central nervous system (CNS) tumors in Western countries. Though they are related in embryonic origin to gonadal GCTs, which are considered highly treatable with cisplatin-based chemotherapy regimens, intracranial GCTs vary in malignant potential and sensitivity to radiation and chemotherapy, generally carrying a worse prognosis. Metastases of intracranial GCTs outside of the CNS are rare, indicate a poor prognosis, and their salvage treatment is not well established.

Whole brain proton irradiation in adult Sprague Dawley rats produces dose dependent and non-dependent cognitive, behavioral, and dopaminergic effects.

Proton radiotherapy causes less off-target effects than X-rays but is not without effect. To reduce adverse effects of proton radiotherapy, a model of cognitive deficits from conventional proton exposure is needed. We developed a model emphasizing multiple cognitive outcomes.

Practice Patterns Among Radiation Oncologists Treating Pediatric Patients With Proton Craniospinal Irradiation.

Purpose: Craniospinal irradiation (CSI) is an important component of therapy for many pediatric central nervous system malignancies. Proton therapy is increasingly available and used for minimizing radiation exposure to normal tissues. The absence of an exit dose with proton therapy mandates decisions regarding coverage of the vertebral bodies (VB) in non-skeletally mature patients.

Sentinel lymph node biopsy in head and neck rhabdomyosarcoma.

Head and neck rhabdomyosarcoma lymph node staging is challenging due to varied patterns of lymphatic drainage and the suboptimal predictive value of available imaging modalities. Furthermore, regional relapse rates are unacceptably high, and the toxicity of empiric radiation is undesirable in the pediatric and young adult population. In an attempt to improve locoregional control without excess morbidity, we have adopted routine sentinel lymph node biopsy in head and neck rhabdomyosarcoma, which is safe and feasible in pediatric patients.

Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors.

Purpose: There are sparse data defining the dose response of radiation therapy (RT) to the hypothalamus and pituitary in pediatric and young adult patients with brain tumors. We examined the correlation between RT dose to these structures and development of endocrine dysfunction in this population.

Materials And Methods: Dosimetric and clinical data were collected from children and young adults (< 26 years of age) with brain tumors treated with proton RT on three prospective studies (2003 to 2016).

Cancer Cell Metabolism: Implications for X-ray and Particle Radiation Therapy.

Advances in radiation delivery technologies and immunotherapy have improved effective cancer treatments and long-term outcomes. Experimental and clinical trials have demonstrated the benefit of a combination of radiation therapy and immunotherapy for tumor eradication. Despite precise radiation dose delivery that is achievable by particle therapy and benefits from reactivating the antitumor immune response, resistance to both therapeutic strategies is frequently observed in patients.

STING, DCs and the link between innate and adaptive tumor immunity.

Cancer and the immune system are intimately related. Much of the bulk of tumors is comprised of stromal leukocytes with immune functions, which serve to both promote and inhibit tumor growth, invasion and metastasis. The T lymphocytes of the adaptive immune system are essential for tumor immunity, and these T cells are generated by cross-priming against tumor associated antigens.

Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis.

Introduction: We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM).

Materials And Methods: All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined.

Combinations of immunotherapy and radiation in cancer therapy.

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models.

Myeloid-derived cells in tumors: effects of radiation.

The discrepancy between the in vitro and in vivo response to radiation is readily explained by the fact that tumors do not exist independently of the host organism; cancer cells grow in the context of a complex microenvironment composed of stromal cells, vasculature, and elements of the immune system. As the antitumor effect of radiotherapy depends in part on the immune system, and myeloid-derived cells in the tumor microenvironment modulate the immune response to tumors, it follows that understanding the effect of radiation on myeloid cells in the tumor is likely to be essential for comprehending the antitumor effects of radiotherapy. In this review, we describe the phenotype and function of these myeloid-derived cells, and stress the complexity of studying this important cell compartment owing to its intrinsic plasticity.

The tailless complex polypeptide-1 ring complex of the heat shock protein 60 family facilitates cross-priming of CD8 responses specific for chaperoned peptides.

The tailless complex polypeptide-1 ring complex (TRiC) is a eukaryotic heat shock protein 60 (hsp60) molecule that has been shown to bind N-terminally extended precursors of OVA-derived SIINFEKL in vivo. Binding of peptides to TRiC was shown to be essential for their presentation on MHC class I. We demonstrate in this study that purified TRiC binds antigenic peptides in vitro as well; however, such binding is not restricted to N-terminally extended peptides, suggesting that the results obtained in vivo reflect the availability of peptides in vivo rather than structural constraints of TRiC-peptide binding.

Specific immunogenicity of heat shock protein gp96 derives from chaperoned antigenic peptides and not from contaminating proteins.

The peptide-binding property of MHC is central to adaptive immunological functions. A similar property of heat shock proteins (HSPs) hsp70 and hsp90 has been implicated in Ag presentation by MHC and in cross-priming. The peptide-binding pocket of hsp70 has been characterized structurally and functionally and a peptide-binding site in gp96 (of hsp90 family) has been defined.