Nonpersistent Nanoarchitectures Enhance Concurrent Chemoradiotherapy in an Immunocompetent Orthotopic Model of HPV+ Head/Neck Carcinoma.

Cisplatin chemoradiotherapy (CRT) is the established standard of care for managing locally advanced human papillomavirus-positive head/neck carcinoma. The typically young patients may suffer serious and long-time side effects caused by the treatment, such as dysphagia, and hearing loss. Thus, ensuring a satisfactory post-treatment quality of life is paramount.

Antitumor Effect by Either FLASH or Conventional Dose Rate Irradiation Involves Equivalent Immune Responses.

Purpose: The capability of ultrahigh dose rate FLASH radiation therapy to generate the FLASH effect has opened the possibility to enhance the therapeutic index of radiation therapy. The contribution of the immune response has frequently been hypothesized to account for a certain fraction of the antitumor efficacy and tumor kill of FLASH but has yet to be rigorously evaluated.

Methods And Materials: To investigate the immune response as a potentially important mechanism of the antitumor effect of FLASH, various murine tumor models were grafted either subcutaneously or orthotopically into immunocompetent mice or in moderately and severely immunocompromised mice.

KRAS inhibition using MRTX1257: a novel radio-sensitizing partner.

Background: KRAS activating mutations are considered the most frequent oncogenic drivers and are correlated with radio-resistance in multiple cancers including non-small cell lung cancer (NSCLC) and colorectal cancer. Although KRAS was considered undruggable until recently, several KRAS inhibitors have recently reached clinical development. Among them, MRTX849 (Mirati Therapeutics) showed encouraging clinical outcomes for the treatment of selected patients with KRAS mutated NSCLC and colorectal cancers.

Optimal dosing regimen of CD73 blockade improves tumor response to radiotherapy through iCOS downregulation.

Background: Irradiation (IR) and immune checkpoint inhibitor (ICI) combination is a promising treatment modality. However, local and distance treatment failure and resistance can occur. To counteract this resistance, several studies propose CD73, an ectoenzyme, as a potential target to improve the antitumor efficiency of IR and ICI.

Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues.

Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes.

Cytofluorometric characterization of the myeloid compartment of irradiated mouse tumors.

The use of ionizing radiation (IR) is a cornerstone for the treatment of cancer and radiotherapy (RT) is used in roughly 50% of cancer patients. It is now well established that RT exerts widespread effects on the tumor stroma, including the immune environment. Together with its deeply characterized effects on the lymphoid compartment, RT also deeply affects the myeloid cell compartment.

Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

Chimeric antigen receptor (CAR)-T cells have demonstrated significant improvements in the treatment of refractory B-cell malignancies that previously showed limited survival. In contrast, early-phase clinical studies targeting solid tumors have been disappointing. This may be due to both a lack of specific and homogeneously expressed targets at the surface of tumor cells, as well as intrinsic properties of the solid tumor microenvironment that limit homing and activation of adoptive T cells.

TGFβ receptor inhibition unleashes interferon-β production by tumor-associated macrophages and enhances radiotherapy efficacy.

Background: Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFβ with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFβ participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations.

Methods: We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer.

Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis.

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus-host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme BFasL, EomesTCF-1, PD-1CD8 Tc1 cells.

COVID-19-Associated Pneumonia: Radiobiological Insights.

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants).

Low Doses of Radiation Increase the Immunosuppressive Profile of Lung Macrophages During Viral Infection and Pneumonia.

Purpose: Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown.

NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis.

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF)-β1/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2).

Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages.

Background: Macrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.

Methods: Since we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.

Differential therapeutic effects of PARP and ATR inhibition combined with radiotherapy in the treatment of subcutaneous versus orthotopic lung tumour models.

Background: Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, although these models are poor surrogate models of human cancers.

Methods: We compared the antitumour efficacy of the combination of ionising radiation (IR) with two DNA damage response inhibitors, the PARP inhibitor olaparib and the ATR inhibitor AZD6738 (ceralasertib), in subcutaneous versus orthotopic cancer models.

Results: Olaparib delayed the growth of irradiated Lewis lung carcinoma (LL2) subcutaneous tumours, in agreement with previous reports in human cell lines.

Radiotherapy-immunotherapy combinations - perspectives and challenges.

Ionizing radiation has historically been used to treat cancer by killing tumour cells, in particular by inducing DNA damage. This view of radiotherapy (RT) as a simple cytotoxic agent has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumour environment by modulating the immune response. Such evidence gives a strong rationale for the use of immunomodulators to boost the therapeutic value of RT, introducing the era of 'immunoradiotherapy'.

Macrophages in radiation injury: a new therapeutic target.

Radiotherapy can induce toxicity in healthy tissues such as radiation-induced fibrosis (RIF), and macrophages are proposed as new profibrogenic cells. In this Point-of-View, we summarize the role of the immune response in ionizing radiation injury, and we focus on macrophages as a new therapeutic target in RIF.

Expanding the therapeutic index of radiation therapy by normal tissue protection.

Normal tissue damages induced by radiation therapy remain dose-limiting factors in radiation oncology and this is still true despite recent advances in treatment planning and delivery of image-guided radiation therapy. Additionally, as the number of long-term cancer survivors increases, unacceptable complications emerge and dramatically reduce the patients' quality of life. This means that patients and clinicians expect discovery of new options for the therapeutic management of radiation-induced complications.

CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages.

Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF.

Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFβ1 cascade involved in fibrogenesis.

Aim: Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications.