Clonal Hematopoiesis is Associated With Protection From Alzheimer\u27s Disease

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer\u27s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 1

Vaccine-based immunotherapy for glioblastoma using tumor cells, Zika virus, and a checkpoint inhibitor

Glioblastoma multiforme (GBM), the most common malignant brain tumor, is very aggressive with a survival rate of less than 5% at five years, despite the current treatment regimen comprised of surgical resection, radiation therapy, and chemotherapy with temozolomide. New and more effective cancer treatments may stem from immunotherapies, which amplify and modify the immune response to target tumor cells. These immunotherapies include checkpoint inhibitors, vaccines, and oncolytic viruses. When used as standalone treatments for GBM, they moderately promote survival and remission. However, combinations of immunotherapies may act synergistically. This project aims to generate a more effective treatment for GBM that employs dual immunotherapies: a checkpoint inhibitor and a cancer vaccine. In a GL261 mouse model of malignant gliomas, we found that this combination yields an overall survival of 75%, compared to a survival rate of 25% with the vaccine alone. Our results suggest that the additional checkpoint inhibitor attenuates tumor-driven immunosuppression and improves survival without apparent toxic effects. While this may encourage the addition of more immunotherapies into a single treatment for GBM, closer evaluation of chemotoxicity is necessary before a finalized treatment is viable for clinical trials. Nonetheless, our findings demonstrate the promising efficacy of combining immunotherapies.This research was supported by the Undergraduate Research Opportunities Program (UROP)

Immunotherapy and checkpoint inhibitors for gliomas

Glioma treatments are faced with challenges, including the inability to fully eliminate cancer stem cells, the immunosuppressive tumor microenvironment, and the blood brain barrier. Although progress has been made with surgical, radiation, and chemotherapies, prognosis for patients remains poor. Rapidly emerging immunotherapies may be able to address the challenges that conventional techniques cannot. Immunotherapies manipulate the patient’s immune system to selectively combat malignancies. Therapies often work to enhance T-cell and natural killer (NK) cell function, which can both eliminate tumor cells and enhance remission. Vaccines encourage in vivo development of anti-tumor T-cells and NK cells, while adoptive transfer techniques focus on engineering immune cells ex vivo before reintroducing them to patients. Vaccine and adoptive transfer therapies have been shown to induce enhanced immune responses in patients but have not always correlated with improved outcomes, likely because of the tumor immunosuppressive microenvironment. Checkpoint inhibitors can impair these tumor immunosuppressive capabilities. Although no one treatment has been able to consistently eliminate gliomas and maintain remission, combinations of vaccines or adoptive transfer techniques in conjunction with immune checkpoint inhibitors offers promise

A platform-independent AI tumor lineage and site (ATLAS) classifier

Abstract Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98–99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary

Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells

Clonal hematopoiesis is associated with protection from Alzheimer’s disease

Clonal hematopoiesis of indeterminate potential (CHIP) is a premalignant expansion of mutated hematopoietic stem cells. As CHIP-associated mutations are known to alter the development and function of myeloid cells, we hypothesized that CHIP may also be associated with the risk of Alzheimer’s disease (AD), a disease in which brain-resident myeloid cells are thought to have a major role. To perform association tests between CHIP and AD dementia, we analyzed blood DNA sequencing data from 1,362 individuals with AD and 4,368 individuals without AD. Individuals with CHIP had a lower risk of AD dementia (meta-analysis odds ratio (OR) = 0.64, P = 3.8 × 10−5), and Mendelian randomization analyses supported a potential causal association. We observed that the same mutations found in blood were also detected in microglia-enriched fraction of the brain in seven of eight CHIP carriers. Single-nucleus chromatin accessibility profiling of brain-derived nuclei in six CHIP carriers revealed that the mutated cells comprised a large proportion of the microglial pool in the samples examined. While additional studies are required to validate the mechanistic findings, these results suggest that CHIP may have a role in attenuating the risk of AD. MAIN: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated expansion of hematopoietic stem cells (HSCs) found in 10–30% of those older than 70 (refs. 1,2,3,4). It most commonly occurs due to truncating or loss-of-function mutations in transcriptional regulators such as DNMT3A, TET2 and ASXL1 and can be detected by sequencing of DNA from peripheral blood or bone marrow cells5. As these are also founding mutations for hematological neoplasms such as acute myeloid leukemia, it is unsurprising that CHIP associates with a higher risk of developing these cancers1,2,6,7. However, CHIP also associates with an increased risk of atherosclerotic cardiovascular disease and death8,9,10. This link is believed to be causal as mice that are deficient for Tet2 or Dnmt3a in hematopoietic cells develop more severe cardiovascular phenotypes, possibly due to altered gene expression in mutant macrophages, which favors the more rapid progression of the lesions8,11,12. Alzheimer’s disease (AD) remains a leading cause of morbidity and mortality in the elderly, but therapies that can effectively slow or halt its progression are lacking. Genome-wide association studies (GWAS) have implicated functional alterations of microglia (MG), the macrophage-like hematopoietic cells in the brain, as a major driver of AD risk13. Because CHIP-associated mutations influence the function of myeloid cells8,11,14, we tested whether CHIP was associated with the risk of AD. RESULTS: Association between CHIP and AD dementia.To test the association between CHIP and incident AD dementia, we used data from the Framingham Heart Study (FHS) and the Cardiovascular Health Study (CHS), which are two cohorts within the Trans-omics for Precision Medicine (TOPMed) project15. CHIP variants (Supplementary Table 1) were identified from blood-derived whole-genome sequencing (WGS) data as previously described9. AD dementia was diagnosed when participants met the criteria of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the AD and Related Disorders Association (ADRDA) for definite, probable or possible AD. After excluding those with coronary heart disease, stroke or prior dementia, there were 2,437 participants in FHS, of whom 92 developed incident AD dementia, and 743 participants in CHS, of whom 166 developed incident AD dementia (Supplementary Table 2). Participants in CHS were substantially older on average and a higher proportion was female compared to participants in FHS, which contributed to a higher rate of AD dementia in CHS compared to FHS (22.3% versus 3.8%) in the follow-up period (Supplementary Table 2). Contrary to our expectations, the presence of CHIP was associated with a lower subdistribution hazard ratio (SHR) for incident AD dementia in fully adjusted competing risks regression (CRR) models (SHR = 0.69, P = 0.13 in CHS; SHR = 0.51, P = 0.068 in FHS; SHR = 0.63, P = 0.024 in a fixed-effects meta-analysis of the two cohorts), while the effects of age, sex and APOE genotype were as expected based on prior studies (Fig. 1a). APOE genotype was strongly associated with AD dementia risk in those without CHIP age 60 years or older (P = 8.1 × 10−8 by log-rank test), but not in CHIP carriers of the same age (P = 0.42 by log-rank test) (Fig. 1b), possibly due to smaller sample size. The inclusion of MG-associated germline polymorphisms from AD GWAS did not attenuate the effect of CHIP in these models (Supplementary Table 3)