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Cancer cells block T cell activation, but new treatment restores immune defenses

Cancer cells block T cell activation, but new treatment restores immune defenses

 


New findings reveal how cancer manipulates immune pathways and highlight therapeutic strategies to unleash T cells against even the most resistant tumors.

Research: Cancer cells evade immunity by inhibiting monocyte-mediated T cell stimulation. Image credit: Shutterstock AI / Shutterstock.com

study: Cancer cells evade immunity by inhibiting monocyte-mediated T cell stimulation. Image credit: CI Photos / Shutterstock.com

In a recent study published in natureResearchers are studying how cancer cells deactivate immune defenses by interfering with the stimulation of T cells that are important for targeting tumors. Researchers investigated the interactions of cancer cells and monocytes in the tumor microenvironment, investigated how oncogenic signaling and inflammatory processes impair immune responses, and investigated the potential for restoring immunity. identify appropriate treatment strategies.

Targeting the tumor microenvironment

The immune system plays a central role in detecting and eliminating cancer. Cytotoxicity or CD8+ T cells, known for their ability to kill infected and cancer cells, require activation and differentiation within specialized niches in the tumor microenvironment to effectively target tumors.

For example, conventional dendritic cells are involved in CD8 activation.+ T cells. However, new research suggests that other immune cells, such as monocytes, may also contribute to this process.

Monocytes can go into an inflammatory state, thereby helping to stimulate T cells. However, the mechanisms involved in this process are still unclear. Oncogenic signaling pathways in cancer cells can disrupt these processes by altering the tumor microenvironment and subsequently promoting immune evasion. Certain cancer cells can also produce signals that polarize the tumor microenvironment to suppress the immune response, thereby complicating symptoms. immunotherapy effort.

Despite recent advances, the cellular and molecular mechanisms involved in intratumoral T cell activation, particularly in resistant tumors, remain unclear.

About research

In this study, the following mouse models were used. melanoma To investigate immune interactions in the tumor microenvironment, we conducted studies in tumors that were responsive or resistant to immunotherapy. The immune composition and functional status of these tumors were analyzed using single-cell ribonucleic acid (RNA) sequencing, immunofluorescence imaging, and flow cytometry.

Additional approaches include adoptive T cell transfer (ACT), which introduces activated T cells into tumors, and genetic modification of cancer cells to explore molecular pathways that influence immunity. The goal of these experiments was to create tumors with specific mutations, expose them to immune attack, and compare their behavior.

By analyzing how monocytes exist, antigen The researchers identified the importance of cross-dressing, the process by which monocytes acquire and present tumor antigens.

We have engineered tumor-derived factors such as prostaglandin E2 (PGE2) and type I interferon (IFN-I) to elucidate their role in shaping the tumor microenvironment. A variety of interventions have been utilized, including blocking PGE2 production and enhancing the IFN-I pathway using genetic and pharmacological methods.

Human melanoma and lung cancer datasets were investigated to identify similarities to this. alive Research results. To this end, we applied spatial transcriptomics to map immune cell interactions in patient samples. Treatment strategies combining immunotherapy and modulators of the PGE2 or IFN-1 pathways were also tested for their ability to restore T cell activity in resistant tumors.

Research results

Cancer cells subvert immune responses by suppressing monocyte-mediated T cell activation in the tumor microenvironment. Specifically, inflammatory monocytes play an important role in stimulating CD8.+ T cells by antigen presentation. However, this process is impaired in tumors with hyperactivation of oncogenic mitogen-activated protein kinase (MAPK) signaling.

This MAPK signaling results in increased production of PGE2 and decreased production of IFN-I, which collectively disrupt the inflammatory monocyte state and suppress cytotoxic T cell stimulation. However, we found that blocking PGE2 production in resistant tumors restored monocyte-mediated T cell activation and alleviated immunosuppression. Enhanced IFN-1 signaling similarly renews the immune response and promotes the presence of inflammatory monocytes, thereby supporting T cell proliferation.

Cross-dressing refers to the process by which monocytes acquire major histocompatibility complex (MHC) class I peptides from tumor cells and is central to T cell activation. This process was found to be intact only in tumors with an immunopermissive tumor microenvironment.

In human melanoma samples, macrophages colocalized with activated T cells within immune hubs, thereby supporting the relevance of these findings across species. Combining PGE2 inhibition with IFN-1 enhancement altered the tumor microenvironment.

conclusion

This study reveals a critical role for inflammatory monocytes in T cell activation and demonstrates how cancer cells evade immunity through dysregulation of PGE2 and IFN-I. Targeting the MAPK pathway to reduce PGE2 and improve IFN-I levels may reverse immune-resistant cancer cells.

These results suggest that by disrupting cancer-induced immune evasion mechanisms, it is possible to restore T cell-mediated immunity even in resistant tumors and increase the efficacy of immunotherapy. Therefore, combining treatments that target these immune resistance mechanisms has the potential to improve outcomes for patients with immunotherapy-resistant cancers.

Reference magazines:

  • Elewort, A., Esteville, G., Beyerl, F., Others. (2024). Cancer cells evade immunity by inhibiting monocyte-mediated T cell stimulation. nature. doi:10.1038/s41586024082574

Sources

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