The Blum Lab aims to develop safer and more effective immunotherapy strategies for patients with solid tumors. Using patient samples, systems immunology, and disease-relevant model systems, we investigate the cellular and molecular drivers of treatment resistance and toxicity across the tumor immunity cycle. Our long-term goal is to uncover broadly applicable principles that can improve clinical outcomes by (Theme 1) overcoming resistance to immunotherapy in the tumor microenvironment and (Theme 2) minimizing the side effects of immunotherapies while preserving anti-tumor immunity.
Model for improving outcomes for cancer patients receiving immunotherapy. Each step of the tumor immunity cycle (adapted from Mellman I, et al. Immunity 2023) presents an opportunity to identify safe, tumor-specific mechanisms that can improve both the safety and efficacy of cancer immunotherapy.
The examples below illustrate current projects within these broader themes.
Theme 1: Improving Immune Responses in Patients with Malignant Effusions
The spread of cancer to the chest and peritoneal cavities can lead to the development of fluid collections known as malignant effusions. These effusions occur in roughly one in five patients with solid tumors. The development of effusions is associated with severe symptoms and poor response to systemic therapies, including immune checkpoint inhibitors (ICIs). Because current treatments are not effective, patients frequently undergo procedures to drain the fluid in liter-scale volumes, and this fluid is typically thrown away as waste. We believe that the cancer cells, immune cells, and liquid components of malignant effusions can instead serve as a window into the human immune response to cancer.
We have focused initially on patients with gastric cancer and effusions in the abdomen, which is known as malignant ascites. However, we have developed a framework and a biobank that can be used to study the range of metastatic cancers that lead to the development of malignant effusions. Our effort has focused on two main areas:
- Defining novel biology: Using single-cell transcriptomics and proteomics, we defined key immune features of malignant ascites from patients with stomach and esophagus cancer. Most notably, we identified a population of dendritic cells that express the gene RORC (RORC DCs) and are enriched in malignant ascites across tumor types and in lymph node metastases. RORC DCs resemble murine RORγt+ DCs/Thetis cells that promote immune tolerance, and they had not previously been associated with cancer in humans or mice. The lab is looking to further understand the biology of RORC DCs and the effusion microenvironment.
- Nominating novel therapeutic strategies: We are using patient-derived ex vivo models to dissect the biology of the ascites microenvironment and nominate new therapeutic strategies for either local (i.e., intraperitoneal) or systemic therapy.
This program aims to improve outcomes for patients with malignant effusions by using clinically accessible tumor material to define mechanisms of immune resistance and identify therapeutic strategies that may be broadly applicable across solid tumors.
Theme 2: Investigating Immune-Related Adverse Events (irAEs) and Anti-Tumor Immunity
Immune-related adverse events (irAEs) are potentially dangerous side effects of immune checkpoint inhibitors. irAEs can affect any organ system and range in severity from mild to life-threatening. The molecular drivers, clinical risk factors, and optimal management strategies for severe irAEs remain poorly defined. Current treatments for severe irAEs rely on broadly immunosuppressive medications, which can compromise tumor control and may not optimally treat the mechanisms driving the organ-specific irAE. Current projects include:
- irAEs and their relationship to anti-tumor immunity: Our first major irAE project focused on ICI-related myocarditis (irMyocarditis), a highly lethal irAE affecting the heart. We leveraged heart, tumor, and blood samples from patients with irMyocarditis to define the cellular landscape of this disease. Our data also suggest that irAEs and anti-tumor responses are distinct, supporting the possibility that they can be therapeutically disentangled. We are extending this framework to irAEs affecting other organs to identify relevant mechanisms and translatable biomarkers, create novel model systems, and identify optimal therapies.
- Clinical features and risk factors: Through the MGH Severe Immunotherapy Complications (SIC) Service, we have evaluated the effect of a multidisciplinary clinical service on outcomes for patients who develop irAEs and identified tumor location as a novel risk factor for severe irAEs. Our studies have identified clinical, laboratory, and host factors associated with irAEs and immunotherapy efficacy, including the presence of tumor deposits in organs affected by irAEs.
Together, these efforts are designed to identify mechanisms and nominate treatments that mitigate irAEs while maximizing anti-tumor immunity.
Select Publications
Blum SM*, Chan TL*, Smith NP*, et al., Reynolds G**, Klempner SJ**, Villani AC**. Multiomic analysis of malignant ascites defines RORC-expressing dendritic cells at sites of metastasis. Sci Immunol. 2026. In press.
Zhao JJ, Lee CK, Chan ASY, Blum SM, et al., Rha SY, Sundar R. Spatial organisation of tumor-infiltrating B-cells informs immune checkpoint inhibitor response in Claudin 18.2-expressing gastric cancer. Clin Cancer Res. 2026. PubMed
Blum SM*, Ouyang B*, Zubiri L, et al., Reynolds KL**, Sullivan RJ**. Tumor location as a risk factor for severe immune-related adverse events. J Immunother Cancer. 2025;13(5):e011312. PubMed
Blum SM*, Zlotoff DA*, Smith NP*, Kernin IJ*, Ramesh S*, et al., Thomas MF**, Neilan TG**, Reynolds KL**, Villani AC**. Immune responses in checkpoint myocarditis across heart, blood and tumour. Nature. 2024;636(8041):215-223. PubMed
Blum SM, Rouhani SJ, Sullivan RJ. Effects of immune-related adverse events (irAEs) and their treatment on antitumor immune responses. Immunol Rev. 2023;318(1):167-178. PubMed
*Co-first authors. **Co-senior authors. Complete list of publications (My NCBI)
Acknowledgments
We are grateful to all of the patients who donate samples for our research and their families. This generosity makes our work possible. We are also deeply appreciative of our funders for supporting our research efforts.
Current support
- National Institute of Allergy and Infectious Diseases Career Development Award (K08AI197864)
- American Association for Cancer Research
- The Torrey Coast Foundation
- Debbie’s Dream Foundation
Prior support
- National Institutes of Health training grant (T32CA071345)
- Dana-Farber/Harvard Cancer Center K12 Clinical Oncology Development Program (K12CA087723)
- MGH American Cancer Society Institutional Research Grant (IRG-21-130-10)