The significance of inhibitory immune checkpoint expression by macrophages and their impact on the immunological landscape of oral squamous cell carcinoma

• Applicant: Dr. Ann-Kristin Struckmeier
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549224982

The response rate among oral squamous cell carcinoma patients treated with immune checkpoint inhibitors currently stands at 25%, a figure that falls short of satisfaction. Furthermore, the majority of patients inevitably develop resistance over the course of treatment. Observations suggest that non-responsive patients undergoing PD-1 inhibitor therapy exhibit distinct redundant macrophage populations. Additionally, anti-PD-1 inhibition prompts the upregulation of specific macrophage subsets, fostering a pro-tumoral environment. These recent discoveries raise questions about the significance of inhibitory immune checkpoints expressed on tumor-associated macrophages (TAMs), particularly concerning the wider tumor microenvironment. They also provoke contemplation regarding whether the expression of inhibitory immune checkpoints by TAMs serves as a pivotal mechanism in primary or secondary resistance to immune checkpoint inhibitors, notably under PD-1 inhibitor therapy.The primary objective of this project is to assess the expression of various inhibitory immune checkpoints within the dynamic tumor microenvironment, with a specific focus on TAMs. Given the preliminary findings, comprehensive genotyping and immunophenotyping are imperative. To achieve this, we will employ techniques such as single-cell RNA sequencing, fluorescence-activated cell sorting, and cytometric bead arrays. Subsequently, we will investigate the impact of single and combined immune checkpoint inhibition on TAM phenotype, with particular emphasis on immune checkpoint expression and, additionally, cytokine profiles. The outcomes of this study are expected to provide foundational insights for subsequent research endeavors aimed at demonstrating causal relationships between TAMs, tumor progression, and responses to immune checkpoint inhibitor treatments in vivo, achieved through manipulations of macrophage numbers and functions.Given the established significance of immune checkpoint-expressing macrophages in various diseases such as sepsis, hepatitis B, and diabetes mellitus, the anticipated results hold relevance not only within the realm of oncology but also for advancing diagnostic and therapeutic strategies across other medical conditions.

• DFG Programme: Research Grants