Barbara Maier

Tumor Immunology and the Tumor Microenvironment

Our research group investigates the complex immune interactions within the tumor microenvironment (TME) of solid tumors, with a focus on mechanisms of immune suppression and tumor immune evasion. Our overarching goal is to overcome the current limitations of cancer immunotherapy by designing new strategies that reprogram specific immune cell subsets to promote robust, tumor-targeted immune responses.

We aim to develop next-generation immunotherapies by modulating antigen-presenting cells (APCs) and other key immune components. Central questions driving our research include:

• How can we empower APCs to prime effective tumor-specific T cell responses?
• What APC phenotypes influence T cell polarization and restimulation at the tumor site?
• How do these interactions contribute to or limit T cell exhaustion?
• What are the key drivers of T cell dysfunction in both the TME and the draining lymph nodes?
• Which signaling pathways in tumor-associated myeloid cells need to be targeted to reverse immune suppression?

To address these questions, we use an integrative approach combining high-throughput cell culture systems, in vivo models, single-cell transcriptomics, and immune profiling of patient-derived tumor samples.
 

Understanding the Tumor Microenvironment (TME)

The tumor microenvironment of solid cancers is a highly immunosuppressive space influenced by factors such as cytokines, hypoxia, nutrient deprivation, metabolic waste, apoptotic cell debris, and a specialized extracellular matrix. These conditions impair the function of both immune and stromal cells, creating a setting in which tumors evade immune surveillance.

Beyond cancer cells themselves, diverse immune populations—including monocytes, macrophages, fibroblasts, dendritic cells, regulatory T cells, and exhausted T cells—contribute to the establishment of the immunosuppressive TME. Our work focuses on targeting immunosuppressive myeloid phenotypes and enhancing the effectiveness of established immunotherapies such as immune checkpoint blockade (ICB). Ultimately, we aim to map the cellular, molecular, and spatial determinants that either support or inhibit effective anti-tumor immunity.
 

Antigen-Specific T Cell Responses in Cancer

Effective tumor-directed T cell responses are essential for successful cancer immunotherapy. However, in many cases, T cells become exhausted within the tumor microenvironment and lose their ability to eliminate tumor cells. These exhausted T cells are characterized by diminished cytokine production, reduced cytotoxic function, and a reliance on persistent antigen exposure.

We study how interactions with different tumor-associated APCs affect T cell differentiation, exhaustion, and memory formation. Specifically, we explore how various APC subsets and their phenotypes influence the quality and durability of antigen-specific T cell immunity, with the aim of improving T cell reactivation in tumors.
 

Immune Checkpoint Blockade (ICB) in Solid Tumors

Immune checkpoint blockade therapies, especially those targeting the PD-1/PD-L1 axis, have transformed treatment options for lung cancer and other solid tumors. Yet, their mechanisms of action are not fully understood, and only a subset of patients responds to ICB.

Emerging evidence suggests that PD-L1 expression on both tumor cells and infiltrating immune cells plays a role in therapy outcomes. Our group investigates:

• Which antigen-presenting cell types mediate responses to ICB
• Whether effective responses require APC–T cell interactions in the draining lymph nodes or at the tumor site
• What stages of T cell maturation are targeted by PD-1/PD-L1 blockade

By dissecting the immune mechanisms behind ICB resistance and response, we aim to inform the development of more effective, personalized immunotherapies.

Barbara Maier studied molecular biology at the University of Vienna and obtained her PhD from MedUni Vienna, working on deciphering the role of type I interferon in pulmonary inflammation under the mentorship of Professor Sylvia Knapp. She focused on bacterial infections in the lung and peritoneum and the protective or detrimental roles of inflammatory mediators therein. She then continued her training as a postdoctoral fellow in the laboratory of Professor Miriam Merad at the Icahn School of Medicine at Mount Sinai in New York (USA). There, she gained extensive knowledge of human tumor immunology and myeloid components of tumor immune suppression. In her main work, she uncovered a regulatory module expressed in dendritic cells in human non-small-cell lung cancer patients, functionally validated multiple of these regulatory molecules, and showed that modulating the regulatory program in dendritic cells leads to improved tumor control. Barbara Maier joined CeMM as a principal investigator in January 2021. Her lab focuses on tumor immunology and specifically on the dynamics of antigen-presenting cell/T-cell interactions in the tumor microenvironment and tumor-draining lymph nodes and how tumor-associated antigen-presenting cell phenotypes shape tumor-directed T-cell responses.

LaMarche, N.M., Hegde, S., Park, M.D. et al. An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis. Nature 2023 Dec 6. (abstract)

Park, M.D., Reyes-Torres, I., LeBerichel, J. et al. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer. Nat Immunol 2023 May; 24:792–801. (abstract)

A Gainullina et al. Network analysis of large-scale ImmGen and Tabula Muris datasets highlights metabolic diversity of tissue mononuclear phagocytes. Cell Rep. 2023 Feb 28;42(2):112046. (abstract)

Fendl B, Berghoff AS, Preusser M, Maier B. Macrophage and monocyte subsets as new therapeutic targets in cancer immunotherapy. ESMO Open. 2023 Feb;8(1):100776. (abstract)

Cohen M, Giladi A, Barboy O, Tanay A, Merad M, Amit I, et al. The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nat Cancer. 2022 Mar;3(3):303-317. (abstract)

Leader A, et al. Single-cell analysis of human non-small cell lung cancer lesions refines tumor classification and patient stratification. Cancer Cell. 2021 Dec 13;39(12):1594-1609.e12. (abstract)

Casanova-Acebes M, et al. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells. Nature. 2021 Jul;595(7868):578-584. (abstract)

Maier B et al. A conserved dendritic cell regulatory program limits antitumor immunity. Nature. 2020 Apr;580(7802):257-262. (abstract)

Ruiz de Galarreta M, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019 Jun 11. (abstract)

Jordan S, et al. Dietary intake regulates the circulating inflammatory monocyte pool. Cell. 2019 Aug. 22. (abstract)