About

Matthew John Atherton is a faculty member in the Biomedical Graduate Studies at the Perelman School of Medicine at the University of Pennsylvania. He holds degrees including BVSc from the University of Bristol and a PhD in Medical Sciences-Infection & Immunity from McMaster University. His clinical expertise is in medical oncology, with a research focus on defining the prognostic and therapeutic role of T cells in hematologic neoplasms through a multi-species comparative approach. He is involved in identifying and appraising novel targets for T cell-based immunotherapy in clinical trials involving canine patients with spontaneous and aggressive tumors, with translational importance for human oncology. His work encompasses the development of immunotherapeutic strategies, including CAR T cell therapies, oncolytic virus-based cancer vaccines, and peptide vaccinations, often utilizing canine models to evaluate therapeutic efficacy and mechanisms. Atherton's contributions include advancing understanding of tumor-infiltrating lymphocytes, cytokine release syndromes, and the tumor microenvironment, with a particular emphasis on immunotherapy for sarcomas, lymphomas, and other cancers.

Research topics

• Medicine
• Immunology
• Cancer research
• Biology
• Virology

Selected publications

• SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-01

  articleOpen access

  Immunosuppressive tumor microenvironment (TME) inactivates CD8+ cytotoxic lymphocytes (CTLs). Here, we identify SPTBN2 spectrin as a key immunosuppressive regulator induced in CTLs in response to nutritional deficit. In human pancreatic and colorectal cancers, SPTBN2 expression negatively correlated with CTL infiltration and patients' survival. In TME of mouse pancreatic and colorectal adenocarcinomas, SPTBN2 inactivated intratumoral CTLs, stimulated tumor growth and conferred cross-resistance to anti-cancer therapies. SPTBN2 knockout protected CAR T-cells from trogocytosis and increased their memory state. SPTBN2 maintained levels of cell surface proteins such as BTLA that undermine CAR T-cell cytotoxicity and promote exhaustion. Re-expression of BTLA largely reversed phenotypes in SPTBN2-deficient CAR T-cells. In manufactured CAR T cells, SPTBN2 was associated with their clinical failure in pediatric patients with leukemia. Accordingly, ablation of SPTBN2 in CAR T-cells increased their cytotoxicity, in vivo persistence and therapeutic effects indicating that SPTBN2 can be targeted to increase the efficacy of anti-cancer therapies.

  PublisherOA PDFDOI

• Immune profiling of canine B cell lymphoma reveals cross-species conservation of prognostic markers

  Scientific Reports · 2025-08-04 · 1 citations

  articleOpen accessSenior author

  Only 60% of patients with diffuse large B cell lymphoma are cured following standard of care therapies. While immune contexture is associated with outcomes in patients treated with chemotherapy, immune mechanisms driving differential therapeutic responses remain unclear. Here, we undertook a comparative analysis of dogs with spontaneous B cell lymphoma (BCL), which exhibit similar dichotomies in therapeutic outcome, to identify conserved and species-specific transcriptional and circulating biomarkers associated with remission duration. In addition, we compared treatment naive and relapsed samples to determine how treatment impacts immune contexture at the time of treatment failure. Among eighteen client-owned dogs with aggressive BCL undergoing multi-agent chemotherapy, comparative immune profiling revealed increased T cell transcripts associated with prolonged remissions and, as in humans, IL2RB expression was associated with favorable outcomes. Increased angiogenic markers were associated with shorter remissions. In treatment naive samples, macrophage associated cytokines were increased, whereas multiple T cell-associated transcripts were enriched in relapsed nodes. Collectively, our findings reveal that changes in immune composition are associated with varying chemotherapeutic outcomes in canine BCL and highlight the potential for comparative oncology approaches to identify factors associated with disease progression, providing insight for development and testing of novel therapeutic approaches.

  PublisherOA PDFDOI

• Younger age is associated with favorable outcomes in adult dogs with hemangiosarcoma receiving adjuvant doxorubicin chemotherapy: results from the PRO-DOX study

  Veterinary oncology. · 2025-12-08 · 2 citations

  articleOpen access

  Abstract Background Canine hemangiosarcoma is a common and aggressive vascular malignancy predominantly affecting dogs over six years of age. Despite surgical resection followed by adjuvant chemotherapy, median survival remains around 4–6 months. Propranolol, a beta-adrenergic receptor (β-AR) antagonist, has shown efficacy in human angiosarcoma, a tumor with similar clinical and morphological characteristics, when combined with chemotherapy. Methods To determine if propranolol could be repurposed as an effective adjunct to chemotherapy, we conducted a phase I clinical study evaluating the safety and efficacy of propranolol combined with doxorubicin (PRO-DOX) in 20 dogs with stage 1 or stage 2 splenic hemangiosarcoma.Plasma from 19 dogs was analyzed for propranolol pharmacokinetics and RNA was extracted from tumors from 13 of the dogs for transcriptional profiling. Results Although propranolol did not appear to influence treatment outcomes, our results revealed long-term survival in young adult dogs (less than 6 years of age), suggesting the possibility of a better response to doxorubicin. Faster clearance of 4-OH propranolol also correlated with long-term survival in younger dogs, but this appeared to be associated with drug metabolism due to age rather than effects of the drug on survival outcomes. Gene expression analysis identified distinct age-associated tumor signatures, with young dogs exhibiting increased immune-related gene expression and older dogs showing elevated expression of genes associated with the cell cycle and the DNA damage response and repair. Conclusions These findings highlight several hallmarks of cellular aging in hemangiosarcoma that may influence treatment responses and long-term survival. Our findings suggest that young adult dogs with splenic hemangiosarcoma treated with doxorubicin have a better prognosis and underscore the need for further research into age-related molecular mechanisms of disease. These insights could refine therapeutic strategies and clinical decision-making in hemangiosarcoma management.

  PublisherOA PDFDOI

• Identification of immune suppressor candidates utilizing comparative transcriptional profiling in histiocytic sarcoma

  Cancer Immunology Immunotherapy · 2025-01-03 · 6 citations

  articleOpen accessSenior author

  Histiocytic sarcoma (HS) is a rare yet lethal malignancy with no established standard of care therapies. A lack of pre-clinical models limits our understanding of HS pathogenesis and identification of therapeutic targets. Canine HS shares multiple clinical and genetic similarities with human HS, supporting its use as a unique translational model. Prior studies have investigated the immunogenicity of HS. Although increased tumor infiltrating lymphocyte (TIL) density is associated with favorable outcomes in canine HS, virtually all canine patients eventually succumb to progressive disease consistent with ultimate failure of anti-tumor immunity. To investigate potential regulators of the immune tumor microenvironment (TME), we undertook a comparative transcriptional approach of three long-lived cases of canine pulmonary HS with heavy T cell infiltrate and three short-lived cases of splenic HS that lacked significant T cell inflammation and compared these data to corresponding grossly normal tissues from dogs undergoing necropsy. This comparison identified PDCD1, encoding the immune checkpoint PD-1, and SPP1, encoding the secreted pro-tumorigenic protein osteopontin, as positive differentially expressed genes (DEGs) in canine HS. TXNIP, encoding the tumor suppressor TXNIP, was the most significant negative DEG. Comparative transcriptomic studies revealed conservation of enriched (including SPP1) and depleted (including TXNIP) DEGs between canine and human HS patients. Immunohistochemistry demonstrated osteopontin in the TMEs of canine and human HS. Collectively, we uncover PD-1, osteopontin, and TXNIP as putative actionable targets in HS and further establish canine HS as a preclinical platform to screen novel immunotherapeutic approaches for this deadly disease.

  PublisherOA PDFDOI

• Younger Age Is Associated with Favorable Outcomes in Adult Dogs with Hemangiosarcoma Receiving Adjuvant Doxorubicin Chemotherapy: Results from the PRO-DOX Study

  Research Square · 2025-05-05

  preprintOpen access
  PublisherOA PDFDOI

• Systemic STING agonist therapy drives expression of interferon stimulated genes and downstream production of cytokines in dogs with solid tumors

  Journal for ImmunoTherapy of Cancer · 2025-12-01

  articleOpen access

  BACKGROUND: Stimulator of interferon genes (STING) agonist drugs can induce expression of interferon stimulated genes (ISGs) and proinflammatory cytokine production aimed to enhance antitumor immunity. The purpose of the current study was to determine the safety, pharmacokinetic, and systemic and intratumoral pharmacodynamic properties of a novel, intravenously delivered STING agonist in client-owned dogs with cancer. METHODS: GSK856, a small-molecule dimeric amidobenzimidazole STING agonist, was administered intravenously to dogs with naturally developing tumors. Patients received two doses of GSK856 1 week apart, followed by definitive-intent surgical tumor removal. RESULTS: 19 dogs diagnosed with various solid tumor types, including malignant melanoma (oral mucosa, n=9; digit, n=1; conjunctiva, n=1), soft tissue sarcoma (5), rhabdomyosarcoma (1), oral fibrosarcoma (1), and mammary squamous cell carcinoma (1), were enrolled. Systemic pharmacokinetic analysis revealed rapid plasma clearance of GSK856 within 30 min of bolus administration. Clinical adverse events of fever, lethargy, and nausea were transient. Concurrent elevation in serum cytokines, including interleukin-6, was consistent with cytokine release syndrome following activation of the STING pathway. Transcriptional analyses of pretreatment and post-treatment blood and tumor tissue revealed robust induction of ISGs. CONCLUSIONS: These data identify tolerated dose levels for a novel, intravenously delivered STING agonist compound that results in on-target effects in systemic and intratumoral immune responses in dogs with solid tumors.

  PublisherOA PDFDOI

• Maximizing the dual benefit of pet dogs in cancer trials

  Nature reviews. Cancer · 2025-01-31 · 1 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• An editorial spotlight on recent progress in veterinary oncology

  Veterinary oncology. · 2025-11-24

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Applications and Opportunities for Immune Cell CAR Engineering in Comparative Oncology

  Clinical Cancer Research · 2024-04-04 · 4 citations

  reviewOpen accessSenior author

  Chimeric antigen receptor (CAR) T-adoptive cell therapy has transformed the treatment of human hematologic malignancies. However, its application for the treatment of solid tumors remains challenging. An exciting avenue for advancing this field lies in the use of pet dogs, in which cancers that recapitulate the biology, immunological features, and clinical course of human malignancies arise spontaneously. Moreover, their large size, outbred genetic background, shared environment with humans, and immunocompetency make dogs ideal for investigating and optimizing CAR therapies before human trials. Here, we will outline how challenges in early clinical trials in patients with canine lymphoma, including issues related to autologous CAR T-cell manufacturing, limited CAR T-cell persistence, and tumor antigen escape, mirrored challenges observed in human CAR T trials. We will then highlight emerging adoptive cell therapy strategies currently under investigation in dogs with hematological and solid cancers, which will provide crucial safety and efficacy data on novel CAR T regimens that can be used to support clinical trials. By drawing from ongoing studies, we will illustrate how canine patients with spontaneous cancer may serve as compelling screening platforms to establish innovative CAR therapy approaches and identify predictive biomarkers of response, with a specific emphasis on solid tumors. With increased funding for canine immunotherapy studies, multi-institutional investigations are poised to generate highly impactful clinical data that should translate into more effective human trials, ultimately benefiting both human and canine cancer patients.

  PublisherOA PDFDOI

• Malignant transformation and subsequent leptomeningeal carcinomatosis of a gastric polyp in a dog

  Journal of Veterinary Internal Medicine · 2024-04-08 · 2 citations

  articleOpen access

  Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.

  PublisherOA PDFDOI

Frequent coauthors

• Jonathan Pol

  Inserm

  20 shared

• Nicola J. Mason

  17 shared

• Brian D. Lichty

  McMaster University

  16 shared

• Kyle B. Stephenson

  15 shared

• Guido Kroemer

  Assistance Publique – Hôpitaux de Paris

  13 shared

• Yonghong Wan

  Children's Hospital of Chongqing Medical University

  12 shared

• John C. Bell

  Ottawa Hospital Research Institute

  11 shared

• Jean‐Simon Diallo

  Ottawa Hospital

  9 shared

Education

• PhD

  McMaster University

• MVM

  University of Glasgow

• BVSc

  University of Bristol