By Dr. Chinta SidharthanReviewed by Benedette Cuffari, M.Sc.Dec 4 2024
New findings reveal how cancer manipulates immune pathways and highlight therapeutic strategies to unleash T-cells against even the most resistant tumors.
Study: Cancer cells impair monocyte-mediated T-cell stimulation to evade immunity. Image Credit: CI Photos / Shutterstock.com
In a recent study published in Nature, researchers investigate how cancer cells inactivate immune defenses by disrupting the stimulation of T-cells, which are critical for targeting tumors. The researchers examine the interplay between cancer cells and monocytes in the tumor microenvironment, explore how oncogenic signaling and inflammatory processes impair immune responses, and identify potential therapeutic strategies to restore immunity.
Targeting the tumor microenvironment
The immune system plays a central role in detecting and eliminating cancer. Cytotoxic or CD8+ T-cells, known for their ability to kill infected and cancer cells, require activation and differentiation within specialized niches of the tumor microenvironment to effectively target tumors.
Conventional dendritic cells, for example, are involved in the activation of CD8+ T-cells. However, emerging research suggests that other immune cells, such as monocytes, may also contribute to this process.
Monocytes can transition into inflammatory states, thereby aiding in T-cell stimulation; however, the mechanisms involved in this process remain unclear. Oncogenic signaling pathways in cancer cells can disrupt these processes by modifying the tumor microenvironment and subsequently promoting immune evasion. Certain cancer cells can also produce signals that polarize the tumor microenvironment to suppress immune responses, thus complicating immunotherapy efforts.
Despite recent advancements, the cellular and molecular mechanisms involved in intra-tumoral T-cell activation, especially in resistant tumors, remain unclear.
About the study
The present study utilized murine models of melanoma with tumors that were either responsive or resistant to immunotherapy to investigate immune interactions in the tumor microenvironment. The immune composition and functional states of these tumors were analyzed using single-cell ribonucleic acid (RNA) sequencing, immunofluorescence imaging, and flow cytometry.
Additional experimental approaches included adoptive T-cell transfer (ACT), during which activated T-cells were introduced to tumors, and the genetic modification of cancer cells to explore the molecular pathways affecting immunity. The goal of these experiments was to create tumors with specific mutations and expose them to immune challenges to compare their behavior.
By analyzing how monocytes present antigens and interact with T-cells, the researchers determined the significance of "cross-dressing," a process where monocytes acquire and present tumor antigens.
Tumor-derived factors such as prostaglandin E2 (PGE2) and type I interferons (IFN-I) were altered to elucidate their roles in shaping the tumor microenvironment. Various interventions were utilized, such as blocking PGE2 production and enhancing IFN-I pathways using genetic and pharmacological methods.
Human melanoma and lung cancer datasets were explored to identify parallels with the in vivo study findings. To this end, spatial transcriptomics was applied to map immune cell interactions in patient samples. Therapeutic strategies that combined immunotherapies with modulators of PGE2 or IFN-I pathways were also tested for their ability to restore T-cell activity in resistant tumors.
Study findings
Cancer cells disrupt immune responses by suppressing monocyte-mediated T-cell activation in the tumor microenvironment. Specifically, inflammatory monocytes play a critical role in stimulating CD8+ T-cells through antigen presentation; however, this process is impaired in tumors with hyperactive oncogenic mitogen-activated protein kinase (MAPK) signaling.
This MAPK signaling leads to increased production of PGE2 and reduced production of IFN-I, which collectively interfere with the inflammatory monocyte state and suppress stimulation of cytotoxic T-cells. However, blocking PGE2 production in resistant tumors was found to restore monocyte-mediated T-cell activation and reduce immune suppression. Enhancing IFN-I signaling similarly renewed the immune responses and promoted the presence of inflammatory monocytes, thereby supporting T-cell proliferation.
Cross-dressing, which refers to a process in which monocytes acquire peptide-major histocompatibility complex (MHC) class I from tumor cells, is central to T-cell activation. This process was found to be intact only in tumors with immune-permissive tumor microenvironments.
In human melanoma samples, macrophages co-localized with activated T-cells in immune hubs, thereby supporting the relevance of these findings across species. Combining PGE2 inhibition and IFN-I enhancement transformed the tumor microenvironment.
Conclusions
The current study reveals the critical role of inflammatory monocytes in T-cell activation and demonstrates how cancer cells evade immunity through PGE2 and IFN-I dysregulation. Targeting the MAPK pathway to reduce PGE2 and improve IFN-I levels can potentially reverse immune resistance cancer cells.
These results suggest that disrupting cancer-driven immune evasion mechanisms can restore T-cell-mediated immunity and enhance the effectiveness of immunotherapies, even in resistant tumors. Thus, combining therapies that target these immune resistance mechanisms has the potential to improve patient outcomes in immunotherapy-resistant cancers.
Journal reference: Elewaut, A., Estivill, G., Bayerl, F., et al. (2024). Cancer cells impair monocyte-mediated T cell stimulation to evade immunity. Nature. doi:10.1038/s41586024082574