Biology subjects

Wisdom, A. J.

Publications and source records attributed to Wisdom, A. J..

8 recordsLinked to original sources

bioRxiv2026

Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma

Glioblastomas (GBMs) are uniformly fatal brain tumors resistant to immunotherapy, yet the mechanisms driving immune dysfunction remain poorly understood. Here we identify a tissue-specific mechanism of dendritic cell (DC) dysfunction contributing to GBM immune evasion. We demonstrate that while systemic immunity depends on type 1 conventional DCs (cDC1s), GBMs preferentially accumulate cDC2s with impaired antigen-presenting capacity. Further, microglia-derived GAS6 and PROS1 signaling through the AXL receptor on DCs suppresses DC activation and, critically, migration to tumor-draining lymph nodes. Pharmacologic AXL inhibition enhances DC migration and consequently anti-tumor immunity. Importantly, radiation therapy activates cDC1-mediated endogenous immune responses, which synergizes with mRNA vaccination to promote complete and durable immune-mediated tumor regression. These findings establish DC-mediated immunity as a therapeutic target in brain tumors and reveal a synergistic mechanism for combining radiation with personalized cancer vaccines.

cancer biology↗

bioRxiv2025

Differential Impact of Lymphocytes on Radiation Response in Autochthonous versus Transplant Sarcomas in Syngeneic Mice

Preclinical studies in transplant tumor models showing high cure rates with combined radiotherapy (RT) and immunotherapy have rarely translated to clinical success, and studies in autochthonous tumor models are limited. We hypothesized that lymphocytes differentially affect RT response in transplant versus autochthonous tumor models. Here, we compared tumor onset and growth delay after 0 or 20 Gy for autochthonous versus transplant soft tissue sarcomas in Rag2-/- mice lacking an adaptive immune system versus immune-intact Rag2+/- mice. While time to tumor onset did not differ between Rag2-/- and Rag2+/- mice in the autochthonous model, transplant tumor onset was significantly slower in immunocompetent mice. No transplant tumors in Rag2-/- mice or autochthonous tumors were cured by RT, whereas 30.4% of Rag2+/- mice with transplant tumors were cured. These results highlight the importance of including autochthonous tumors as complementary model systems to study the interplay between the immune system and RT response.

cancer biology↗

bioRxiv2024

Enhancing radiotherapy response via intratumoral injection of the TLR9 agonist CpG to stimulate CD8 T cells in an autochthonous mouse model of sarcoma

Radiation therapy is frequently used to treat cancers including soft tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to radiation therapy (RT) in transplanted tumors, but the mechanism(s) remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and two doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to RT + CpG, we performed bulk RNA-seq, single-cell RNA-seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and interferon-{gamma}. CpG + RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG + RT, TCR clonality analysis suggests an increase in clonal T-cell dominance. Collectively, these findings demonstrate that RT + CpG significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft tissue sarcoma.

cancer biology↗

bioRxiv2023

Loss of function of Atrx leads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma

The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenic KrasG12D and loss of function mutations of Trp53 and Atrx. In this model, we demonstrate that the loss of Atrx contributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss of Atrx and activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action.

cancer biology↗

bioRxiv2023

Both CD8 and CD4 T cells contribute to immunosurveillance preventing the development of neoantigen-expressing autochthonous sarcomas

The adaptive immune system plays an essential anti-tumor role through immunosurveillance and response to immunotherapies. Characterizing phenotypic features and mechanisms of dysfunction of tumor-specific T cell populations may uncover novel immunotherapeutic targets and biomarkers of response. To study tumor-specific T cell responses in vivo, a tumor model must express a known neoantigen. While transplant models with known neoantigen expression are widely available, autochthonous tumor models in which the tumor coevolves with the immune system are limited. In this study, we combined CRISPR/Cas9 and sleeping beauty transposase technology to develop an autochthonous orthotopic murine sarcoma model with oncogenic KrasG12D, functionally impaired p53, and expression of known MHCI and MHCII sarcoma neoantigens. Using MHC tetramer flow cytometry, we identified a tumor-specific immune response in the peripheral blood as early as 10 days after tumor induction leading to tumor clearance. Tumors developed at high penetrance after co-depletion of CD8 and CD4 T cells, but depletion of either CD8 or CD4 T cells alone was insufficient to permit tumor growth. These results suggest that CD8 and CD4 T cells can independently contribute to immunosurveillance leading to clearance of sarcomas expressing MHCI and MHCII neoantigens.

cancer biology↗

bioRxiv2021

Atrx deletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx deleted tumors are more sensitive to radiation therapy. In the absence of Atrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find that Atrx deleted sarcomas have a reduced adaptive immune response, impaired cGAS-STING signaling, and increased sensitivity to an oncolytic herpesvirus therapy. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.

cancer biology↗

bioRxiv2020

Digoxin Targets Central Carbon Metabolism and Remodels the Tumor Microenvironment

Cancer therapies targeting metabolism have been limited due to a lack of understanding of the controlling properties of vulnerable pathways. The Na+/K+ ATPase is responsible for a large portion of cellular energy demands but how these demands influence metabolism and create metabolic liabilities are not known. Using metabolomic approaches, we first show that digoxin, a cardiac glycoside widely used in humans, acts through disruption to central carbon metabolism via on target inhibition of the Na+/K+ ATPase that was fully recovered by expression of an allele resistant to digoxin. We further show in vivo that administration of digoxin inhibits glycolysis in both malignant and healthy cells, particularly within clinically relevant cardiac tissue, while exhibiting tumor-specific cytotoxic activity in an allografted soft tissue sarcoma. Single-cell expression analysis of over 31,000 cells within the sarcoma shows that acute Na+/K+ ATPase inhibition shifts the immune composition of the tumor microenvironment, leading to selective alterations to metabolic programs in specific immune cells thus acting both through tumor cell and microenvironmental (e.g. macrophage) cells. These results provide evidence that altering energy demands can be used to regulate glycolysis with cell-type specific consequences in a multicellular environment of biomedical interest.

cancer biology↗

bioRxiv2020

A single cell atlas reveals distinct immune landscapes in transplant and primary tumors that determine response or resistance to immunotherapy

Despite impressive responses in some patients, immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Nearly all preclinical immunotherapy studies utilize transplant tumor models, but cure rates of transplant tumor models treated with immunotherapy often overestimate patient responses. Here, we show that transplant tumors are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous tumors. We generated a single-cell atlas of tumor-infiltrating immune cells from transplant and primary tumors treated with radiation and immunotherapy, which reveals striking differences in their immune landscapes. Although radiotherapy remodels myeloid cell phenotypes in primary and transplant tumors, only transplant tumors are enriched for CD8+ T cells that mediate tumor clearance while mice with primary sarcomas demonstrate tumor-specific tolerance. These results identify distinct microenvironments in tumors that coevolve with the immune system, which promote tolerance that must be overcome for immune-mediated cancer cures.

cancer biology↗