Abstract 4999: GFRAL is not required for PDAC tumor development and TME immune cell suppression

Abstract Growth Differentiation Factor 15 (GDF15) is a stress-induced cytokine upregulated in several cancers, including pancreatic cancer. Its most well-known role is signaling through GFRAL in the brain to induce an anorexia/cachexia syndrome. Outside the brain, GDF15 acts as an immunosuppressor. In cancer, GDF15 is thought to leverage this function to protect tumors from immune surveillance. Recently, much attention has been drawn to the relationship between GDF15 and T cell activity, as blocking GDF15 has been shown to enhance responses to anti-PD-1 therapies. Interestingly, the only known receptor for GDF15 is GFRAL, whose expression is restricted to a subpopulation of neurons located in the brainstem. As GDF15 emerges as a target for enhancing immune cell activity, the role of GFRAL in this relationship remains underexplored in animal models of cancer. The purpose of this study is to evaluate the necessity of GFRAL in mediating the immunosuppressive activity of GDF15 with relevance to pancreatic ductal adenocarcinoma (PDAC), the most aggressive form of pancreatic cancer. To test this, T cells were isolated from the whole spleen of immunocompetent mice and activated in the presence of conditioned media (CM) from murine KPC PDAC cells (PdxCre; Kras+/G12D; Trp53fl/fl). In culture, we find that CM containing GDF15 suppressed the proliferation of CD4 and CD8 T cells. qRT-PCR confirmed that T cells lack GFRAL expression, suggesting that GDF15-mediated suppression of T cell activity does not require its canonical receptor. Additionally, KPC CM equally inhibited the proliferation of T cells isolated from GFRAL+/+ and GFRAL−/- mice. We previously showed that GDF15 is required for early-stage development of pancreatic cancer in mice. To determine if this function of GDF15 is mediated through GFRAL, KPC cells were orthotopically injected into the pancreas of immunocompetent GFRAL+/+ and GFRAL−/- mice. No significant differences in tumor burden or overall survival were observed between GFRAL+/+ and GFRAL−/- mice at the experimental endpoint. In addition, both GFRAL+/+ and GFRAL−/- mice exhibited similar myeloid and lymphoid immune responses to tumor implantation compared to non-tumor controls. Moreover, expression of the T cell exhaustion marker PD-1 remained consistent between groups. These results suggest that GDF15 modulates the tumor microenvironment independently of its sole known receptor, GFRAL. Further, disruption of the GDF15-GFRAL signaling axis does not alter the immune cell landscape or enhance T cell expansion. These findings provide valuable insights into the immunomodulatory function of GDF15 in PDAC and the possible distinct roles that the GDF15-GFRAL signaling axis has in regulating anorexia/cachexia vs tumorigenesis. Citation Format: Emma Crockett Funk, Abasi-ama Udeme, Cynthia F. Wright, Jenna Schwesig, Michael C. Ostrowski, Teresa A. Zimmers, Leonidas G. Koniaris, David Wang, Denis C. Guttridge. GFRAL is not required for PDAC tumor development and TME immune cell suppression abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4999.