Immunomodulatory impact of PTPN11/SHP2-based vertical RAS-MAPK pathway inhibition in pancreatic cancer
Protein tyrosine phosphatase non-receptor 11 (PTPN11/SHP2) is a critical upstream mediator of RAS-MAPK signaling and a central node in adaptive resistance mechanisms evolving with RAS and MEK/ERK inhibition. Accordingly, clinical trials are currently evaluating allosteric SHP2 inhibitors in vertical RAS pathway combination therapies for various KRAS-mutant malignancies, including pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to delineate the immunomodulatory effects of SHP2-based vertical RAS pathway inhibition in notoriously immunotherapy-refractory PDAC, spanning from early treatment response to invariably evolving adaptive resistance. Employing human and murine PTPN11 knockout and wild-type PDAC cell lines, an autochthonous murine PDAC model (KPC), and patient-derived PDAC organoids, we find that short term dual MEK/SHP2 inhibition induces increased T cell infiltration and a reduction in immunosuppressive M2-like macrophages. However, these effects are accompanied by a decrease in mature dendritic cells and a concomitant expansion of monocytic myeloid-derived suppressor cells, indicative of a mixed immunological response with both immune-activating and immune-suppressing features. These changes are associated with tumor cell-intrinsic upregulation of CXCR3 ligands and TGF-{beta}, as well as increased expression of checkpoint ligands for TIGIT and TIM-3 across molecular subtypes and species. With prolonged treatment and transition to an adaptive resistant tumor cell state, the initial immune-sensitizing effects are lost and the immune-suppressive features prevail. M2-like macrophages re-accumulate, dendritic cell maturation remains impaired, TGF-{beta} expression persists, and TIGIT and TIM-3 ligand expression is further enhanced. Notably, dual SHP2/RAS inhibition recapitulates the observed induction of TGF-{beta} and checkpoint ligands. Collectively, these findings identify a dynamic but ultimately immunosuppressive remodeling of the tumor microenvironment in response to SHP2-based vertical RAS pathway inhibition in PDAC and provide a rationale for combinatorial immunotherapy strategies. In particular, concurrent targeting of TGF-{beta}, combined TIGIT/TIM-3 checkpoint blockade, and likely CD40 agonism may help sustain early immune activation while counteracting emerging suppressive features, thereby improving the durability of tumor control.