Recent advances in immunotherapy research have revealed crucial roles for new immune cells in combating cancer, leading to potential strategies to enhance treatment efficacy and overcome resistance.
Immunotherapy has transformed cancer treatment, providing new hope for cancers once deemed incurable by harnessing the immune system to fight the disease. However, many cancers can evade immune attacks, leading to resistance against these treatments. Researchers led by Anna Obenauf at the IMP have identified a critical role for inflammatory monocytes—an immune cell type—in reactivating T cells to attack cancer cells within tumors. Published in Nature, these findings position monocytes as a promising target to enhance immunotherapy, with the potential to benefit patients battling cancers such as melanoma, lung, pancreatic, and colorectal cancer.
The Evolution of Immunotherapy
Over the past few decades, immunotherapy has revolutionized cancer treatment, providing effective options for diseases once thought to be untreatable, including melanoma, lung cancer, and bladder cancer. What began as experimental research in laboratories has now transitioned into life-changing clinical applications, offering new hope for patients with difficult-to-treat conditions.
How Immunotherapy Works
Immunotherapy works by utilizing the body’s immune system to target and destroy cancer cells. This is achieved either by broadly boosting immune activity or by focusing on specific pathways that help the immune system recognize, attack, and eliminate cancer cells.
Despite its significant advancements, immunotherapy still faces major challenges. A key obstacle is cancer’s ability to evade the immune system by altering its cells to escape detection and creating an immune-suppressive environment within the tumor. As a result, many patients do not respond to current treatments—for instance, more than 50% of those diagnosed with melanoma, the most aggressive type of skin cancer, see limited or no benefit.
Advanced Research in Cancer Immunotherapy
Much of how cancer evades the immune response remains unknown, largely due to the complex cascade of molecular events in the interactions between cancer and immune cells. Understanding the nuances of these processes will be key to developing more effective therapies.
In a study led by Anna Obenauf, Senior Group Leader at the IMP, an international team of researchers integrated cutting-edge tools, including melanoma mouse models, single-cell RNA sequencing, and advanced functional genetics and imaging technologies, to push the boundaries of our understanding of the immune system’s role in fighting cancer.
The study, now published in the journal Nature, reveals an additional type of immune cell involved in stimulating the immune response against cancer, opening up possibilities for new strategies to boost immunotherapy and potentially expand its benefits to more patients.
Rethinking the Cancer Immunity Cycle
Researchers studying the body’s antitumor defenses often refer to the ‘cancer immunity cycle’—a series of steps through which immune cells recognize and eliminate cancer cells. At the core of this cycle are T cells, the immune system’s primary cancer-fighting cells. But T cells do not work alone; they rely on activation from other immune cells, particularly antigen-presenting cells (APCs) such as dendritic cells–the main T cell activators.
The process begins when cancer cells release protein fragments, or antigens, that are captured by APCs. These cells present the antigens to T cells, effectively ‘priming’ them to recognize cancer cells as targets. Once activated in the lymph nodes, T cells travel to the tumor site to destroy it, releasing new antigens that restart the cycle of immune activation.
“The cancer immunity cycle, as we understand it today, is actually incomplete—we’re missing the crucial step of T cell reactivation within the tumor microenvironment,” says Anais Elewaut, co-first author of the study and a student in the Vienna BioCenter PhD Program. “We discovered that when T cells reach the tumor, they still need additional activation from other immune cells to be fully effective.”
Novel Findings and Future Directions
To identify the missing components in this process, the scientists used powerful cell models to investigate the factors that make cancer susceptible to the most common immunotherapies.
Two melanoma cell line models derived from mice that respond differently to commonly used therapies were generated at the Obenauf lab: one that responds well to both immunotherapy and targeted therapy, which applies substances aimed at specific cancer cells; the other resistant to both these treatment types. “With this system, we could closely compare responsive to resistant tumors, helping us figure out the key factors that determine whether a treatment will succeed or fail.”
Monocytes: A New Player in Cancer Immunity
The team first analyzed the tumor environment in both models by profiling gene expression at the level of single cells, and then sorted and quantified immune cell types based on specific markers on their surface. “We were very interested when we noticed lots of monocytes in responsive tumors compared to resistant ones. Monocytes are a type of immune cell never reported to play a role in T cell stimulation,” explains Elewaut. For the longest time, researchers had been looking at dendritic cells as the main activators of T cells, overlooking the role of other immune cells. In contrast, the resistant model had few monocytes, but was filled with suppressive macrophages, which are known to inhibit immune responses.
“Monocytes were thought to play a limited role in cancer immunity,” explains Guillem Estivill, co-first author of the study and a student in the Vienna BioCenter PhD Program. “Now we show how the presence or absence of these specific immune cells can lead to very different treatment outcomes.” Whereas dendritic cells are critical for kickstarting the cancer immunity cycle in the lymph node, both dendritic cells and monocytes are needed to fully activate T cells in the tumor.
The scientists found that monocytes can directly ‘borrow’ parts of cancer cells, including antigens, and present them to T cells. This process, called ‘cross-dressing’, allows monocytes to reactivate T cells, which boosts their function in recognizing and attacking cancer cells.
Restoring Immune Balance Against Cancer
The study also shows how cancer cells evade immunity by making it harder for T cells to stay activated and perform effectively. Cancer cells increase production of the molecule prostaglandin E2, which blocks the action of both monocytes and dendritic cells. Simultaneously, cancer cells decrease the production of interferons—molecules that stimulate immune activity— thereby further weakening the immune system’s ability to fight the tumor. “We’ve seen that restoring the levels of these molecules brings T cells back to their cancer-killing action through the activation of monocytes,” explains Estivill.
Building on this discovery, one promising strategy will be to use COX inhibitors, such as aspirin—drugs that block the cyclooxygenase (COX) enzyme, which is responsible for producing molecules that cause inflammation such as prostaglandin E2. Additionally, stimulating interferon production could enhance the immune system’s ability to combat cancer. These approaches could be combined with existing immunotherapies, providing new tools against cancers that are currently resistant to treatment.
The findings make monocytes promising targets to boost immunotherapies, with insights that have the potential to benefit a wide range of patients affected by cancers with similar molecular pathways to melanoma. These include lung, pancreatic, and colorectal cancer.
Future Directions in Immunotherapy
Future research will focus on exploring how stimulating T cells with monocytes and other immune cells plays out in different forms of immunotherapy. This knowledge could reveal new ways to overcome resistance to immunotherapies. “Clinical trials combining COX inhibitors and immunotherapy are on the horizon. And we already identified strategies to enhance their effectiveness,” says Anna Obenauf. “Our goal is to deepen the mechanistic understanding of anti-tumor immunity. I hope this will help us overcome resistance in more patients, making cancer immunotherapy a viable option for a broader range of patients.”
Reference: “Cancer cells impair monocyte-mediated T cell stimulation to evade immunity” by Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta and Anna C. Obenauf, 27 November 2024, Nature.
DOI: 10.1038/s41586-024-08257-4
Guillem Estivill is a PhD student in Anna Obenauf’s lab at the IMP and a member of the EVOMET network, a renowned European consortium dedicated to studying the evolution of cancer metastasis. Supported by the European Commission’s Innovative Training Networks program under the Marie Skłodowska-Curie Actions, EVOMET is coordinated by the Institute for Research in Biomedicine (IRB) Barcelona and includes thirteen leading academic, clinical, and industrial institutions. This collaborative initiative trains early-career researchers in metastasis biology and therapeutic development. By promoting interdisciplinary and cross-sector collaboration, EVOMET aims to fast-track the development of targeted therapies and improve treatments for metastatic cancer.
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1 Comment
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