Abstract B012: Pan-RAS Inhibition Reprograms T Cell Immunity within the Pancreatic Adaptive Immune Microenvironment
Rashmi J. Kumar, Emily Lasse-Opsahl, Lauren Gerbereux, Carlos E. Espinoza, Jiayue Wang, Jude Ogechukwu Okoye, Timothy L. Frankel, Marina Pasca di MaglianoAbstract
Introduction:
The advent of pan-RAS and allele-specific inhibitors in clinical trials have created an urgent need to understand how RAS inhibition remodels the pancreatic immune microenvironment and alters anti-tumor immunity, to guide rational combinations with immunotherapy.
Methods:
We used a murine model with pancreas-specific, doxycycline-inducible, reversible oncogenic KRAS G12D expression to compare three states: the RAS-ON, RAS-OFF (KRAS G12D-specific genetic inactivation), and the RAS-inhibited (RAS-i) states. RAS-i condition is defined by treatment with the preclinical pan-RAS(ON) inhibitor RMC-7977 (Note: as this is an investigational compound there is no generic drug name). Single-cell sequencing and transcriptomic profiling were used to evaluate immune remodeling in the pancreas. Changes in immune phenotypes discovered through transcriptomic profiling were validated using a custom 25-marker spectral flow cytometry panel in an orthotopic inducible-KRAS G12D pancreatic adenocarcinoma model.
Results:
Single cell sequencing showed expansion of the T cell compartment after RAS inactivation (RAS-OFF) or inhibition (RAS-i) compared with the RAS-ON pancreas, driven primarily by CD8+ T cells. However, CD8+ T cells exhibit distinct transcriptomic changes between RAS-OFF and RAS-i states. Pan-RAS inhibition increased recruitment of naive T cells into the pancreatic microenvironment but was associated with limited differentiation into cytotoxic effector CD8+ T cells capable of expressing Prf1, Gzmb, and Ifng in the RAS-i cohort. In contrast, the RAS-OFF state promoted robust effector differentiation, including early and late effector populations with upregulation of Fasl, expansion of central memory T cells, and reduced naive T cell abundance. Differential gene analysis shows increased expression of Il7r expression in RAS-OFF versus RAS-i T cells, consistent with enhanced self-renewal and clonal expansion capacity. Orthogonal validation with spectral flow cytometry confirmed these transcriptomic findings: the RAS-OFF state contained a higher proportion of CD3+CD8+CD62LLowCD44High effector T cells compared to RAS-i. Consistently, a significant fraction of CD8+ T cells in the RAS-i cohort remained CD62LHigh naive T cells. Moreover, orthotopic tumor burden was highest in RAS-ON, lowest in RAS-OFF tumors, with an intermediate burden after RAS-i.
Conclusion:
Taken together, pan-RAS inhibition remodels the pancreatic immune microenvironment resulting in diminished CD8+ T cell effector abundance and functionality, as a potential consequence of systemic pan-RAS inhibition. Comparatively, RAS-OFF, with KRAS G12D allele-specific inactivation, shows increased T cell recruitment, early activation and successful conversion to effector T cells. These observations suggest that the immunologic consequences of systemic pan-RAS inhibition should be considered when designing RAS inhibitor-immunotherapy combinatorial therapies for pancreatic cancer.
Citation Format:
Rashmi J. Kumar, Emily Lasse-Opsahl, Lauren Gerbereux, Carlos E. Espinoza, Jiayue Wang, Jude Ogechukwu Okoye, Timothy L. Frankel, Marina Pasca di Magliano. Pan-RAS Inhibition Reprograms T Cell Immunity within the Pancreatic Adaptive Immune Microenvironment [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 B012.