Blood Cancer Biology and Immunotherapy
Tumor Immunology • Cancer and Immune Cell Metabolism • Leukemia • Allogeneic Hematopoietic Stem Cell Transplantation • Graft-versus-host disease • Immunotherapy
Our research group studies questions at the intersection of immunology and hematology with the goal of developing improved therapies for patients with blood cancer. We are particularly interested in how metabolic processes in tumor and immune cells govern survival, cell fate and cell-cell interactions. Our team explores basic research questions leveraging a variety of experimental techniques, such as preclinical cancer and stem cell transplantation models, metabolomics, flow cytometry, organoid cultures, and CRISPR-Cas9 gene editing. Our ultimate goal is to generate knowledge with the potential for clinical translation. We are an international and interdisciplinary team dedicated to mentoring and supporting the next generation of scientists in tumor immunology and hematology.
Cancer and Immunometabolism
Cellular metabolism fulfills diverse essential functions for cell survival, proliferation, differentiation, and functions. Some examples are the cell supply with energy, the synthesis of structural compounds for proliferation, the organization of cell-cell communication, and many more. Importantly, metabolic processes are not just the consequence of a certain cell activation status. Rather, metabolism is a driver of cell fate, and failure to engage essential metabolic pathways results in dysfunction and cell death. Our recent work showed that CD8+ T cells rewired their lipid metabolism upon activation and accumulate saturated phosphoinositides (PI), unlike unactivated T cells, which were rich in polyunsaturated PI. Saturated PI were essential to sustain effector T cell signaling and function by providing the substrate for efficient generation of second messengers. We found that in patients with melanoma, immune checkpoint inhibitor treatment resulted in accumulation of saturated PI in circulating CD8+ T cells, which was associated with clinical response (Edwards-Hicks and Apostolova et al., Nat Immunol 2023, Figure 1).
Our research group is now dedicated to understanding how tumor and immune cell metabolism supports tumor immune evasion. We are specifically interested in acute myeloid leukemia (AML), an aggressive malignant disease of the bone marrow with dismal outcomes. AML can be cured by allogeneic hematopoietic stem cell transplantation (allo-HSCT), an immunotherapeutic treatment modality in which the transferred foreign donor immune system eliminates residual malignant cells in the patient. However, tumor cells employ diverse mechanisms of immune escape leading to relapse. We aim to explore how metabolism of AML cells and T cells contributes to immune evasion. We believe that defining such metabolic vulnerabilities will lay the groundwork for translational studies to boost the anti-tumor immune response in patients receiving cellular immunotherapies for leukemia (Figure 2).
Allogeneic Hematopoietic Stem Cell Transplantation
The second focus area is understanding the biology of immunological complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our past work has investigated the role of metabolic and cell stress reactions in graft-versus-host disease (GVHD), a frequent and severe complication of allo-HSCT (Figure 3). We identified that the ectonucleotidase CD73 reduced the severity of GVHD by generating the anti-inflammatory mediator adenosine and thus inhibiting alloreactive T cell proliferation, migration, and cytokine production (Tsukamoto and Apostolova et al, Blood 2012). Furthermore, we discovered that the bile acid tauroursodeoxycholic acid (TUDCA) reduced intestinal antigen presentation and immune cell activity, and directly protected intestinal epithelial cells from tissue damage. TUDCA improved significantly GVHD outcomes in preclinical models without impairing the anti-tumor immunity (Haring and Uhl et al, Haematologica 2021). Moreover, we found elevated activation of the unfolded protein response (UPR) in tissues of mice and patients with GVHD. Inhibiting the UPR-driven IRE1a cascade improved GVHD outcomes in preclinical models (Haring et al, Haematologica 2022). In our future work, we aim to define novel mechanisms contributing to GVHD development with the ultimate goal to increase the safety and applicability of allo-HSCT.
Connection to Clinical Practice
AML relapse after allogeneic hematopoietic stem cell transplantation
We recently reported the results of a phase II investigator-initiated trial on the efficacy and safety of checkpoint inhibitors with hypomethylating agents in patients with AML relapse after allo-HSCT (Apostolova et al, BJH 2023). We found an overall response rate of 25% with long-term remissions in individual patients. By performing correlative immune phenotyping and experimental studies, we are now working towards identifying the mechanisms of resistance to checkpoint inhibitor treatment.
Immune checkpoint inhibitor-induced adverse events
Checkpoint inhibitors have revolutionized the treatment of patients with solid cancers, inducing long-term remissions in previously incurable diseases. However, checkpoint inhibition can lead to severe immune-related adverse events (irAE, Figure 3). We identified extracorporeal photopheresis (ECP) as an efficient therapeutic approach for patients with adverse events induced by checkpoint inhibitors (Apostolova et al., New Engl J Med 2020). This discovery led to the initiation of a phase I clinical trial (NCT05414552). We hope that our future efforts will establish ECP as an efficient and safe treatment for patients with irAE.
Figure 1. Phosphoinositide (PI) metabolism in CD8 effector T cells. Top panel: During early T cell activation, abundantly activated PLCg1 converts polyunsaturated PI to generate the second messengers DAG and IP3 for T cell signaling. Middle panel: In effector T cells, PLCg1 activation is reduced and de novo synthesis of saturated PI from glucose becomes essential to sustain second messenger levels. Bottom panel: Blocking de novo PI synthesis decreases the levels of second messengers and results in impaired MEK/ERK signaling and CD8 T cell survival, proliferation and function. From: Edwards-Hicks J and Apostolova P et al, Nat Immunol. 2023 Mar;24(3):516-530. Created with Biorender.com
Figure 2. Metabolism as a therapeutic target to boost anti-tumor immunity. Metabolic programs of leukemia cells and immune cells can contribute to immune evasion and leukemia persistence. Our team aims to define metabolic interactions between tumor and immune cells that could be therapeutically targeted to achieve a more efficient anti-tumor T cell response. Created with Biorender.com.
Figure 3. GVHD and immune-related adverse events. Left panel: After an allogeneic hematopoietic stem cell transplantation (allo-HSCT), the donor immune system can attack healthy epithelial cells in the recipient due to the recognition of "foreign" antigens. This cytotoxic reaction is termed graft-versus-host disease (GVHD) and is a frequent and severe complication of allo-HSCT. Right panel: Upon checkpoint inhibitor treatment, the activity of endogenous T cells is boosted. Apart from a beneficial anti-tumor effect, the T cells can elicit immune-related adverse events (irAE) by harming epithelial or connective tissues. Our team is dedicated to achieving a better understanding of the biology of GVHD and irAE to make cancer immunotherapie safer. Image created with Biorender.com