Loss of p53 Attenuates the Contribution of IL-6 Deletion on Suppressed Tumor Progression and Extended Survival in Kras-Driven Murine Lung Cancer

Interleukin-6 (IL-6) is involved in lung cancer tumorigenesis, tumor progression, metastasis, and drug resistance. Previous studies show that blockade of IL-6 signaling can inhibit tumor growth and increase drug sensitivity in mouse models. Clinical trials in non-small cell lung cancer (NSCLC) reveal that IL-6 targeted therapy relieves NSCLC-related anemia and cachexia, although other clinical effects require further study. We crossed IL-6 (-/-) mice with Kras (G12D) mutant mice, which develop lung tumors after activation of mutant Kras (G12D), to investigate whether IL-6 inhibition contributes to tumor progression and survival time in vivo. Kras (G12D); IL-6 (-/-) mice exhibited increased tumorigenesis, but slower tumor growth and longer survival, than Kras (G12D) mice. Further, in order to investigate whether IL-6 deletion contributes to suppression of lung cancer metastasis, we generated Kras (G12D); p53 (flox/flox); IL-6 (-/-) mice, which developed lung cancer with a trend for reduced metastases and longer survival than Kras (G12D); p53 (flox/flox) mice. Tumors from Kras (G12D); IL-6 (-/-) mice showed increased expression of TNFα and decreased expression of CCL-19, CCL-20 and phosphorylated STAT3 (pSTAT3) than Kras (G12D) mice; however, these changes were not present between tumors from Kras (G12D); p53 (flox/flox); IL-6 (-/-) and Kras (G12D); p53 (flox/flox) mice. Upregulation of pSTAT3 and phosphorylated AKT (pAKT) were observed in Kras (G12D) tumors with p53 deletion. Taken together, these results indicate that IL-6 deletion accelerates tumorigenesis but delays tumor progression and prolongs survival time in a Kras-driven mouse model of lung cancer. However, these effects can be attenuated by p53 deletion.