Waking Immune-Resistant Tumors With Neddylation

The CD47/signal regulatory protein α (SIRPα) axis, which functions as an inhibitory phagocytosis checkpoint, also serves as a key mediator in cancer immune evasion. Many cancers, including colorectal cancer (CRC), exploit the expression of CD47 to escape phagocytic clearance and activate the innate immune system. Previous work has indicated that distinct paradigms of posttranslational modifications mediate the regulatory mechanisms of the CD47/SIRPα axis. In this issue of the JCI, Li et al. show that neddylation, a ubiquitin-like modification, inactivates Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), a downstream target of this pathway. They further show that inhibition of SHP2 sensitizes CRC cells to immunotherapies to which they were previously resistant. Collectively, the results underscore the need for cotargeting SHP2 and immune checkpoints (e.g., programmed death 1 [PD1]) in CRC and possibly other immunotherapy-resistant tumors

Meningioma: A review of clinicopathological and molecular aspects

Meningiomas are the most the common primary brain tumors in adults, representing approximately a third of all intracranial neoplasms. They classically are found to be more common in females, with the exception of higher grades that have a predilection for males, and patients of older age. Meningiomas can also be seen as a spectrum of inherited syndromes such as neurofibromatosis 2 as well as ionizing radiation. In general, the 5-year survival for a WHO grade I meningioma exceeds 80%; however, survival is greatly reduced in anaplastic meningiomas. The standard of care for meningiomas in a surgically-accessible location is gross total resection. Radiation therapy is generally saved for atypical, anaplastic, recurrent, and surgically inaccessible benign meningiomas with a total dose of ~60 Gy. However, the method of radiation, regimen and timing is still evolving and is an area of active research with ongoing clinical trials. While there are currently no good adjuvant chemotherapeutic agents available, recent advances in the genomic and epigenomic landscape of meningiomas are being explored for potential targeted therapy

Cancer immunotherapy based on MUSIC platform and STING activation in brain cancer cells

https://openworks.mdanderson.org/sumexp23/1008/thumbnail.jp

Utilizing CD24 as an indicator for tumor aggressiveness and metastasis

https://openworks.mdanderson.org/sumexp23/1020/thumbnail.jp

Self-reported evaluation of competencies and attitudes by physicians-in-training before and after a single day legislative advocacy experience

BACKGROUND: Advocacy is increasingly being recognized as a core element of medical professionalism and efforts are underway to incorporate advocacy training into graduate and undergraduate medical school curricula. While limited data exist to quantify physician attitudes toward advocacy, even less has been done to assess the knowledge, skills, and attitudes of future physicians. The purpose of this study was to assess students’ experiences and attitudes toward legislative advocacy, cutting out using a convience sample. METHODS: A paper survey based on previously validated surveys was administered to a convenience sample of premedical and medical student participants attending a National Advocacy Day in Washington, DC, in March 2011, both before and after their advocacy experiences. Responses were anonymous and either categorical ( or ordinal, using a 5-point Likert scale. Data were analyzed statistically to evaluate demographics and compare changes in pre- and post-experience attitude and skills. RESULTS: Data from 108 pre-advocacy and 50 post-advocacy surveys were analyzed yielding a response rate of 46.3%. Following a single advocacy experience, subjects felt they were more likely to contact their legislators about healthcare issues (p = 0.03), to meet in person with their legislators (p < 0.01), and to advocate for populations' health needs (p = 0.04). Participants endorsed an increased perception of the role of a physician advocate extending beyond individual patients (p = 0.03). Participants disagreed with the statement that their formal curricula adequately covered legislative healthcare advocacy. Additionally, respondents indicated that they plan to engage in legislative advocacy activities in the future (p < 0.01). CONCLUSIONS: A one-time practical advocacy experience has a positive influence on students’ knowledge, skills and attitudes towards legislative advocacy. Practical experience is an important method of furthering medical education in advocacy and further research is necessary to assess its impact in a broader population

Immunological Conversion of Solid Tumours Using a Bispecific Nanobioconjugate for Cancer Immunotherapy

Solid tumours display a limited response to immunotherapies. By contrast, haematological malignancies exhibit significantly higher response rates to immunotherapies as compared with solid tumours. Among several microenvironmental and biological disparities, the differential expression of unique immune regulatory molecules contributes significantly to the interaction of blood cancer cells with immune cells. The self-ligand receptor of the signalling lymphocytic activation molecule family member 7 (SLAMF7), a molecule that is critical in promoting the body\u27s innate immune cells to detect and engulf cancer cells, is expressed nearly exclusively on the cell surface of haematologic tumours, but not on solid ones. Here we show that a bispecific nanobioconjugate that enables the decoration of SLAMF7 on the surface of solid tumours induces robust phagocytosis and activates the phagocyte cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, sensitizing the tumours to immune checkpoint blockade. Our findings support an immunological conversion strategy that uses nano-adjuvants to improve the effectiveness of immunotherapies for solid tumours

Healthcare Reform and the Next Generation: United States Medical Student Attitudes toward the Patient Protection and Affordable Care Act

CONTEXT: Over one year after passage of the Patient Protection and Affordable Care Act (PPACA), legislators, healthcare experts, physicians, and the general public continue to debate the implications of the law and its repeal. The PPACA will have a significant impact on future physicians, yet medical student perspectives on the legislation have not been well documented. OBJECTIVE: To evaluate medical students' understanding of and attitudes toward healthcare reform and the PPACA including issues of quality, access and cost. DESIGN, SETTING, AND PARTICIPANTS: An anonymous electronic survey was sent to medical students at 10 medical schools (total of 6982 students) between October-December 2010, with 1232 students responding and a response rate of 18%. MAIN OUTCOME MEASURES: Medical students' views and attitudes regarding the PPACA and related topics, measured with Likert scale and open response items. RESULTS: Of medical students surveyed, 94.8% agreed that the existing United States healthcare system needs to be reformed, 31.4% believed the PPACA will improve healthcare quality, while 20.9% disagreed and almost half (47.7%) were unsure if quality will be improved. Two thirds (67.6%) believed that the PPACA will increase access, 6.5% disagreed and the remaining 25.9% were unsure. With regard to containing healthcare costs, 45.4% of participants indicated that they are unsure if the provisions of the PPACA will do so. Overall, 80.1% of respondents indicated that they support the PPACA, and 78.3% also indicated that they did not feel that reform efforts had gone far enough. A majority of respondents (58.8%) opposed repeal of the PPACA, while 15.0% supported repeal, and 26.1% were undecided. CONCLUSION: The overwhelming majority of medical students recognized healthcare reform is needed and expressed support for the PPACA but echoed concerns about whether it will address issues of quality or cost containment

Single-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target.

A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer

Synthetic Cationic Helical Polypeptides for the Stimulation of Antitumour Innate Immune Pathways in Antigen-Presenting Cells

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses

Adaptive Design of mRNA-Loaded Extracellular Vesicles for Targeted Immunotherapy of Cancer

The recent success of mRNA therapeutics against pathogenic infections has increased interest in their use for other human diseases including cancer. However, the precise delivery of the genetic cargo to cells and tissues of interest remains challenging. Here, we show an adaptive strategy that enables the docking of different targeting ligands onto the surface of mRNA-loaded small extracellular vesicles (sEVs). This is achieved by using a microfluidic electroporation approach in which a combination of nano- and milli-second pulses produces large amounts of IFN-γ mRNA-loaded sEVs with CD64 overexpressed on their surface. The CD64 molecule serves as an adaptor to dock targeting ligands, such as anti-CD71 and anti-programmed cell death-ligand 1 (PD-L1) antibodies. The resulting immunogenic sEVs (imsEV) preferentially target glioblastoma cells and generate potent antitumour activities in vivo, including against tumours intrinsically resistant to immunotherapy. Together, these results provide an adaptive approach to engineering mRNA-loaded sEVs with targeting functionality and pave the way for their adoption in cancer immunotherapy applications