Tumor-Associated Macrophages as Major Immunosuppressive Cells in the Tumor Microenvironment.

Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity.

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections.

Virulent infectious agents such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and methicillin-resistant (MRSA) induce tissue damage that recruits neutrophils, monocyte, and macrophages, leading to T cell exhaustion, fibrosis, vascular leak, epithelial cell depletion, and fatal organ damage. Neutrophils, monocytes, and macrophages recruited to pathogen-infected lungs, including SARS-CoV-2-infected lungs, express phosphatidylinositol 3-kinase gamma (PI3Kγ), a signaling protein that coordinates both granulocyte and monocyte trafficking to diseased tissues and immune-suppressive, profibrotic transcription in myeloid cells. PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm.

Immune Profile of Exosomes in African American Breast Cancer Patients Is Mediated by Kaiso/THBS1/CD47 Signaling.

African American (AA) women with breast cancer are more likely to have higher inflammation and a stronger overall immune response, which correlate with poorer outcomes. In this report, we applied the nanostring immune panel to identify differences in inflammatory and immune gene expression by race. We observed a higher expression of multiple cytokines in AA patients compared to EA patients, with high expression of CD47, TGFB1, and NFKB1 associated with the transcriptional repressor Kaiso.

A Novel CD206 Targeting Peptide Inhibits Bleomycin-Induced Pulmonary Fibrosis in Mice.

Activated M2-polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios, including Idiopathic Pulmonary Fibrosis (IPF). In this study, we investigated the effects of targeting the CD206 receptor in M2-like macrophages with a novel synthetic analogue of a naturally occurring Host Defense Peptide (HDP), RP-832c, to decrease profibrotic cytokines. RP-832c selectively binds to CD206 on M2-polarized bone marrow-derived macrophages (BMDM) in vitro, resulting in a time-dependent decrease in CD206 expression and a transient increase in M1-macrophage marker TNF-α.

PI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation.

Myeloid cells play key roles in cancer immune suppression and tumor progression. In response to tumor derived factors, circulating monocytes and granulocytes extravasate into the tumor parenchyma where they stimulate angiogenesis, immune suppression and tumor progression. Chemokines, cytokines and interleukins stimulate PI3Kγ-mediated Rap1 activation, leading to conformational changes in integrin α4β1 that promote myeloid cell extravasation and tumor inflammation Here we show that PI3Kγ activates a high molecular weight form of myosin light chain kinase, MLCK210, that promotes myosin-dependent Rap1 GTP loading, leading to integrin α4β1 activation.

A Novel CD206 Targeting Peptide Inhibits Bleomycin Induced Pulmonary Fibrosis in Mice.

Activated M2 polarized macrophages are drivers of pulmonary fibrosis in several clinical scenarios such as Acute Respiratory Disease Syndrome (ARDS) and Idiopathic Pulmonary Fibrosis (IPF), through the production of inflammatory and fibrosis-inducing cytokines. In this study, we investigated the effect of targeting the CD206 receptor with a novel fragment of a Host Defense Peptide (HDP), RP-832c to decrease cytokines that cause fibrosis. RP-832c selectively binds to CD206 on M2 polarized bone marrow derived macrophages (BMDM) , resulting in a time-dependent decrease in CD206 expression, and a transient increase in M1 marker TNFα, which resolves over a 24hr period.

Transcriptional repressor Kaiso promotes epithelial to mesenchymal transition and metastasis in prostate cancer through direct regulation of miR-200c.

The loss of miR-200 family, through DNA methylation, results in cancer cells undergoing an epithelial to mesenchymal transition (EMT), and metastasis. In this study, we established that the transcriptional repressor Kaiso directly binds methylated regions of the miR-200 family, and this is reversed with 5-aza treatment. sh-Kaiso PC-3 cells display increased miR-200-a/b/c, miR-141, and miR-429 expression, with miR-200c demonstrating the most significant increase.

Association of Epstein - Barr virus and breast cancer in Eritrea.

Background: The oncogenic potential of Epstein-Barr virus (EBV) in breast cancer is being increasingly recognized. Despite some controversies regarding such role, new evidence is suggesting a culpability of EBV in breast cancer, particularly in Africa where the virus has been originally associated with causation of several solid and hematological malignancies. One example is a report from Sudan implicating EBV as a prime etiologic agent for an aggressive type of breast cancer, where nearly 100% of tumor tissues were shown to carry viral signatures.

Passive proton therapy vs. IMRT planning study with focal boost for prostate cancer.

Background: Exploiting biologic imaging, studies have been performed to boost dose to gross intraprostatic tumor volumes (GTV) while reducing dose elsewhere in the prostate. Interest in proton beams has increased due to superior normal-tissue sparing they afford. Our goal was to dosimetrically compare 3D conformal proton boost plans with intensity-modulated radiation therapy (IMRT) plans with respect to target coverage and avoiding organs at risk.

Commissioning of a proton gantry equipped with dual x-ray imagers and a robotic patient positioner, and evaluation of the accuracy of single-beam image registration for this system.

Purpose: To check the accuracy of a gantry equipped with dual x-ray imagers and a robotic patient positioner for proton radiotherapy, and to evaluate the accuracy and feasibility of single-beam registration using the robotic positioner.

Methods: One of the proton treatment rooms at their institution was upgraded to include a robotic patient positioner (couch) with 6 degrees of freedom and dual orthogonal kilovoltage x-ray imaging panels. The wander of the proton beam central axis, the wander of the beamline, and the orthogonal image panel crosswires from the gantry isocenter were measured for different gantry angles.

Radiographic film dosimetry of proton beams for depth-dose constancy check and beam profile measurement.

Radiographic film dosimetry suffers from its energy dependence in proton dosimetry. This study sought to develop a method of measuring proton beams by the film and to evaluate film response to proton beams for the constancy check of depth dose (DD). It also evaluated the film for profile measurements.

Evaluation of the dosimetric properties of a synthetic single crystal diamond detector in high energy clinical proton beams.

Purpose: To investigate the dosimetric properties of a synthetic single crystal diamond Schottky diode for accurate relative dose measurements in large and small field high-energy clinical proton beams.

Methods: The dosimetric properties of a synthetic single crystal diamond detector were assessed by comparison with a reference Markus parallel plate ionization chamber, an Exradin A16 microionization chamber, and Exradin T1a ion chamber. The diamond detector was operated at zero bias voltage at all times.

Water equivalent thickness analysis of immobilization devices for clinical implementation in proton therapy.

Immobilization devices can impact not only the inter- and intra-fraction motion of the patient, but also the range uncertainty of the treatment beam in proton therapy. In order to limit additional range uncertainty, the water equivalent thickness (WET) of the immobilization device needs to be well known and accurately reflected in the calculations by the treatment planning system (TPS). The method presented here focusses on the use of a nozzle-mounted variable range shifter and precision-machined polystyrene blocks of known WET to evaluate commercial immobilization devices prior to clinical implementation.

Evaluation and comparison of New 4DCT based strategies for proton treatment planning for lung tumors.

Purpose: To evaluate different strategies for proton lung treatment planning based on four-dimensional CT (4DCT) scans.

Methods And Materials: Twelve cases, involving only gross tumor volumes (GTV), were evaluated. Single image sets of (1) maximum intensity projection (MIP3) of end inhale (EI), middle exhale (ME) and end exhale (EE) images; (2) average intensity projection (AVG) of all phase images; and (3) EE images from 4DCT scans were selected as primary images for proton treatment planning.

SU-E-T-238: Annual QA of Proton Gantry with Robotic Table.

Purpose: To perform the annual QA of proton gantry with a robotic table.

Methods: A new proton gantry with robotic table has been commissioned and is being used in clinic for patient treatment. The gantry is equipped with a robotic table with 6-degrees of freedom and dual cardinal angle KV imagers for patient registration.

Water-equivalent path length calibration of a prototype proton CT scanner.

Purpose: The authors present a calibration method for a prototype proton computed tomography (pCT) scanner. The accuracy of these measurements depends upon careful calibration of the energy detector used to measure the residual energy of the protons that passed through the object.

Methods: A prototype pCT scanner with a cesium iodide (CsI(Tl)) crystal calorimeter was calibrated by measuring the calorimeter response for protons of 200 and 100 MeV initial energies undergoing degradation in polystyrene plates of known thickness and relative stopping power (RSP) with respect to water.

Spill-to-spill and daily proton energy consistency with a new accelerator control system.

The Loma Linda University proton accelerator has had several upgrades installed including synchrotron dipole power supplies and a system for monitoring the beam energy. The consistency of the energy from spill-to-spill has been tested by measuring the depth ionization at the distal edge as a function of time. These measurements were made with a minimally equipped beamline to reduce interference from confounding factors.

Leakage and scatter radiation from a double scattering based proton beamline.

Proton beams offer several advantages over conventional radiation techniques for treating cancer and other diseases. These advantages might be negated if the leakage and scatter radiation from the beamline and patient are too large. Although the leakage and scatter radiation for the double scattering proton beamlines at the Loma Linda University Proton Treatment Facility were measured during the acceptance testing that occurred in the early 1990s, recent discussions in the radiotherapy community have prompted a reinvestigation of this contribution to the dose equivalent a patient receives.

Calibration of a proton beam energy monitor.

Delivery of therapeutic proton beams requires an absolute energy accuracy of +/-0.64 to 0.27 MeV for patch fields and a relative energy accuracy of +/-0.

Microdosimetry spectra of the Loma Linda proton beam and relative biological effectiveness comparisons.

Protons have long been recognized as low LET radiation in radiotherapy. However, a detailed account of LET (linear energy transfer) and RBE (relative biological effectiveness) changes with incident beam energy and depth in tissue is still unresolved. This issue is particularly important for treatment planning, where the physical dose prescription is calculated from a RBE using cobalt as the reference radiation.