Abstract B101: Stroma-tumor crosstalk converges with oncogenic KRAS signaling to drive an NFκB-mediated immune evasion program

Abstract

An immunosuppressive tumor microenvironment (TME) is a hallmark of pancreatic ductal adenocarcinoma (PDAC), rendering most tumors resistant to immunotherapy approaches. Importantly, “tumor-to-stroma” crosstalk downstream of oncogenic KRAS has emerged as a major driver of immune evasion in PDAC, however the role of reciprocal “stroma-to-tumor” signaling remains enigmatic. In particular, how stromal signals converge with hyperactive KRAS signaling to influence tumor cell intrinsic immune evasion is largely unknown. To address this, we took advantage of tumor interstitial fluid (TIF), a complex mixture of soluble factors isolated from the PDAC TME, to model stromal signaling to tumor cells. Using a coculture platform that employs tumor cells expressing the model antigen gp33-41and gp33-specific T cells isolated from the P14 T cell receptor transgenic mouse, we demonstrated that TIF treatment rendered PDAC cells resistant to antigen-specific T cell-mediated killing in vitro, recapitulating a key feature of immune resistance observed in PDAC tumors. Given that oncogenic KRAS signaling has been shown to directly impact tumor-intrinsic immune evasion, in part through regulation of FAS ligand expression, we evaluated how pharmacological inhibition of this pathway impacts TIF-induced immune evasion. We find that a selective KRASG12D inhibitor (MRTX-1133) and a multi-selective RAS(ON) inhibitor (RMC-6326) could sensitize TIF-treated tumor cells to T cell killing through both FAS-dependent and FAS-independent mechanisms. Transcriptomic profiling of TIF-induced and KRAS-dependent gene expression identified a number of pathways with known immunomodulatory roles in tumor cells, including the NFκB pathway, which was similarly impacted by KRAS inhibition in vivo. Functionally, we found that pharmacologic inhibition of NFκB can effectively restore T cell-mediated killing in the presence of TIF. Moreover, targeting NFκB downstream effectors, such as COX2 and LIF, can also enhance tumor cell susceptibility to T cell-mediated cytotoxicity. Importantly, inhibition of either NFκB effectors or KRAS signaling enhanced the therapeutic efficacy of adoptive T cell therapy in mouse models of PDAC. Mechanistically, KRAS inhibition was found to have distinct impacts on NFκB target genes, suppressing targets induced by TIF but paradoxically upregulating a distinct subset of TIF-independent NFκB target genes. Moreover, KRAS inhibition failed to completely reverse TIF-induced activation of NFκB target genes, including COX2, suggesting that blockade of the NFkB pathway could further boost KRAS inhibition induced T cell killing. In line with this, combining KRAS and COX2 inhibition further enhanced T cell-mediated killing of TIF-treated tumor cells in vitro. Together, these findings uncover an NFκB immune evasion program that is sustained by both oncogenic KRAS signaling and stromal cues, providing evidence that therapeutic targeting of this tumor-intrinsic axis may improve the efficacy of both immunotherapy and KRAS-targeted therapy in PDAC. Yuwenbin Li, Morgan Truitt, Daniel Cao, Jonathan Zhu, Yang Dai, Mariel Burquez-Escobedo, Gaoyang Liang, Michael Downes, Annette Atkins, Ruth Yu, Ronald Evans. Stroma-tumor crosstalk converges with oncogenic KRAS signaling to drive an NFκB-mediated immune evasion program [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B101.