Details

Autor(en) / Beteiligte

• Norgard, Robert J
• Budhani, Pratha
• O'Brien, Sarah A
• Xia, Youli
• Egan, Jessica N
• Flynn, Brianna
• Tagore, Joshua R
• Seco, Joseph
• Peet, Gregory W
• Mikucka, Ania
• Wasti, Ruby
• Chan, Li-Chuan
• Hinkel, Melanie
• Martinez-Morilla, Sandra
• Pignatelli, Jeanine
• Trapani, Francesca
• Corse, Emily
• Feng, Di
• Kostyrko, Kaja
• Hofmann, Marco H
• Liu, Kang
• Kashyap, Abhishek

Titel

Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with combined SOS1 and MEK Inhibition for Improved Immunotherapy Response

Ist Teil von

• Cancer research communications, 2024-06, Vol.4 (6), p.1548-1560

Ort / Verlag

United States: American Association for Cancer Research

Erscheinungsjahr

2024

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• KRAS inhibitors have demonstrated exciting pre-clinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KRASG12D, p53 mutant, murine PDAC-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intra-tumoral CD8+ T cells without durable responses. scRNA-sequencing revealed an increase in inflammatory cancer associated fibroblasts (iCAFs), M2 macrophages, and a decreased dendritic cell quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor free mice with established immune memory. Our data suggests that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.