Transcriptional response of kidney tissue after 177Lu-octreotate administration in mice

AbstractIntroductionThe kidneys are one of the main dose limiting organs in 177Lu-octreotate therapy of neuroendocrine tumors. Therefore, biomarkers for radiation damage would be of great importance in this type of therapy. The purpose of this study was to investigate the absorbed dose dependency on early transcriptional changes in the kidneys from 177Lu-octreotate exposure.MethodsFemale Balb/c nude mice were i.v. injected with 1.3, 3.6, 14, 45 or 140MBq 177Lu-octreotate. The animals were killed 24h after injection followed by excision of the kidneys. The absorbed dose to the kidneys ranged between 0.13 and 13Gy. Total RNA was extracted from separated renal tissue samples, and applied to Illumina MouseRef-8 Whole-Genome Expression Beadchips to identify regulated transcripts after irradiation. Nexus Expression 2.0 and Gene Ontology terms were used for data processing and to determine affected biological processes.ResultsDistinct transcriptional responses were observed following 177Lu-octreotate administration. A higher number of differentially expressed transcripts were observed in the kidney medulla (480) compared to cortex (281). In addition, 39 transcripts were regulated at all absorbed dose levels in the medulla, compared to 32 in the cortex. Three biological processes in the cortex and five in the medulla were also shared by all absorbed dose levels. Strong association to metabolism was found among the affected processes in both tissues. Furthermore, an association with cellular and developmental processes was prominent in kidney medulla, while transport and immune response were prominent in kidney cortex.ConclusionSpecific biological and dose-dependent responses were observed in both tissues. The number of affected transcripts and biological processes revealed distinct response differences between the absorbed doses delivered to the tissues

Determine the relevance of HPV-specific T-cells in the immune response against the HPV-positive cancers

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Correction to: Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.

Following publication of the original article [1], the author reported that an author name, Roberta Zappasodi, was missed in the authorship list

Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop.

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host\u27s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual\u27s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019

Radiobiological effects of the thyroid gland - transcriptomic and proteomic responses to 131l and 211At exposure

Radionuclides are widely used in medicine. 131I is one of the most employed radionuclides and is administered to patients either bound to tumor targeting molecules or as halide to target the thyroid or thyroid cancer. 211At is proposed for radionuclide therapy and preclinical and clinical research on 211At-labeled tumor targeting molecules is on-going. The thyroid gland accumulates both 131I and 211At as halides and is an organ at risk. Additionally, 131I exposure of thyroid may occur from radioactive fallout from e.g. nuclear accidents. There is a lack of knowledge of molecular mechanisms in thyroid cells after 131I or 211At exposure. The overall aim of this work was to examine the transcriptomic and proteomic effects of 131I and 211At exposure on normal thyroid tissue in vivo. The influence of absorbed dose, dose-rate, time after administration, and radiation quality on gene expression regulation was studied. Another aim was to identify radiation-responsive genes in thyroid. Mice and rats were i.v. injected with 0.064-42 kBq 211At or 9-4700 kBq 131I. Resulting absorbed dose to thyroid from 211At and 131I exposures were 0.023-32 and 0.0058-34 Gy, respectively. Transcriptomic and proteomic responses in thyroid and plasma were measured 1-168 h after administration using RNA microarray and liquid chromatography mass spectrometry, respectively. Fold-change and adjusted p-value cut-offs of 1.5 and 0.01 were used to determine statistically significantly regulated transcripts. Pathway analyses were performed using Gene Ontology and the Ingenuity Pathway Analysis tool (p-value < 0.05). Plasma T4 and TSH levels were measured in rats using ELISA. The transcriptional response in thyroid tissue after 131I and 211At exposure varied with absorbed dose, dose-rate, time after administration, and radiation quality. In mice, 27 recurrently regulated genes were identified after 131I or 211At exposure and genes with similar function shared similar transcriptional regulation patterns. Additionally, regulation of several kallikrein genes was identified in mouse thyroid tissue after 131I or 211At administration. In rats, 2 recurrently genes were identified: Dbp and Slc47a2. Different biological functions were affected in response to different exposure conditions. For example, effects on immune response were found at 1, 6, and 168, but not 24 h after 1.7 kBq 211At administration in mice. An impact on rat thyroid function with regulation of 13 genes crucial for thyroid hormone synthesis was identified. The proteomic response to 32 Gy suggests hypoxia in thyroid and decreased thyroid function. Profound effects on gene expression regulation with distinct differences in response to different exposures were identified in mouse and rat thyroid tissue following 131I or 211At exposure. The transcriptional response likely depends to a varying degree on absorbed dose, dose-rate, time after administration, and radiation quality. Recurrently regulated genes were identified, and the biomarker applicability of these genes should be further assessed

Next-generation CTLA-4 targeting molecules and combination therapy: promising strategies for improving cancer immunotherapy

ABSTRACTRadiation therapy and anti-CTLA-4 combination therapy can induce meaningful responses in some patients. Adding CD40 may provide additional benefit. Next-generation anti-CTLA-4 antibodies, such as botensilimab, are showing promise in clinical trials. Combining botensilimab with RT and/or CD40 agonist may offer additional benefits for challenging tumor types