Role of MIF-CD74 signaling as an immune regulator and therapy target in pancreas cancer.

Background and Innovation: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with limited treatment options. A major barrier to treating PDA is the immune suppression occurring within the tumor microenvironment (TME), which allows tumor cells to evade targeting by the immune system and limits the efficacy of immune checkpoint therapy (ICT). A key contributor to this immunosuppression are tumor-associated macrophages (TAMs) present in the PDA TME. TAMs manifest a spectrum of activation states, ranging from inducing anti- tumor responses to enhancing tumor progression. PDA tumor cells alter this spectrum by recruiting and modulating TAMs to promote immune evasion. This results in a suppression of the anti-tumor T-cell responses critical for effective ICT. Intriguingly, recent studies suggest that TAMs can be "reprogrammed" to activate the immune system and enable adaptative immune responses to target cancer cells. In this context, we identified the MIF-CD74 cytokine signaling axis as a novel regulator of tumor progression in PDA. Our preliminary data indicate that tumor-derived MIF increases TAM recruitment, decreases T-cell infiltration into the TME, and enhances tumor progression. While our data suggest a role for MIF in shaping the PDA TME, the function of MIF and its receptor CD74 in regulating TAM activation, the impact on anti-tumor T-cell responses, and its potential as an immunotherapy target in PDA remain unclear. In this proposal we will delineate how MIF signaling, through CD74 on TAMs, promotes tumor progression by suppressing anti-tumor T-cell responses. In addition, we will develop approaches to target this axis to reprogram TAMs and activate cytotoxic T-cell responses which could enhance immunotherapy efficacy in PDA. Innovation: This project will fill key gaps in our understanding of how MIF-CD74 signaling regulates tumor- immune crosstalk in PDA and provide insights into its potential as a myeloid checkpoint target for immunotherapy with implications that could extend to other cancer types. To this end, we develop novel models that provide direct mechanistic insights into the role of MIF-CD74 signaling in PDA tumor cells (syngeneic MIF knockout tumor lines), TAMs (MacΔCD74 mice), and human tissues (PDOTS). Furthermore, we employ single-cell RNA sequencing techniques to generate novel datasets that will delineate the contribution of MIF-CD74 signaling to immune heterogeneity present in the PDA TME. Finally, we leverage our findings to develop a novel immunotherapeutic strategy that combines MIF-CD74 inhibitors with checkpoint blockade to overcome the limitations of ICT in PDA. Significance and Impact to Veterans Healthcare: The risk of developing PDA is increased in military personal due to the high prevalence of associated risk factors among veterans. In addition, veterans often present late in disease progression where therapeutic options remain limited. This proposal will provide novel insights into the immune regulation of PDA and uncover novel myeloid checkpoint targets for immunotherapy which could be used to improve outcomes in veterans with pancreatic cancer. Path to translation/Implementation: This proposal will provide the pre-clinical basis for investigating MIF inhibition as a potential new immunotherapy approach in PDA. Building on our findings the next step will be to incorporate MIF inhibitor therapy into existing clinical therapies for PDA patients. Monoclonal antibodies to human MIF have been FDA approved for several diseases. In the future, we can assess these therapies in combination with chemo- and immunotherapy backbones for PDA as part of a clinical trial. Project Number: 1I01BX006978-01 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Ravikanth Maddipati | Institution: VA NORTH TEXAS HEALTH CARE SYSTEM, DALLAS, TX | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ONCC-S (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11052061