CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM)

Simple Summary In about 15-18% of breast cancers the HER2 gene is amplified, which allows an anti-HER2 treatment. However, about 50% of HER2-positive patients experience de novo or acquired resistance to the antibody-based therapy with trastuzumab. Therefore, the identification of predictive markers for therapy success and novel combination strategies is needed. Here we explored the impact of CX3CL1 on trastuzumab treatment efficiency and immunological mechanism involved in a humanized tumor mouse model. Trastuzumab treatment showed pronounced efficiency in CX3CL1 overexpressing cancer cells compared to low expressing cells preventing lung metastasis, while the administration of CX3CL1 shedding inhibition did not cause an enhanced treatment effect. Moreover, the application of shedding inhibitors to CX3CL1 overexpression tumors resulted in a slightly enhanced tumor growth. Therefore, the presence of CX3CL1 might predict a pronounced response to trastuzumab therapy in patients and should be investigated in a large cohort of HER2(+) patients. CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells. Moreover, we evaluated the therapeutic capacity of Matrix-Metalloproteinases-inhibitors TMI-1 and GI254023X in combination with the anti-HER2 antibody trastuzumab in vitro and in vivo. TMI-1 and GI254023X caused a reduced shedding of CX3CL1 and of HER2 in vitro but without effects on tumor cell proliferation or viability. In addition, trastuzumab treatment did not retard MDA-MB-453 cell expansion in vitro unless CX3CL1 was overexpressed upon transfection (MDA-MB-453(CX3CL1)). In humanized tumor mice, which show a coexistence of human tumor and human immune system, CX3CL1 overexpression resulted in a slightly enhanced tumor growth. However, trastuzumab treatment attenuated tumor growth of both MDA-MB-453(CX3CL1) and empty vector transfected MDA-MB-453 transplanted mice but showed enhanced efficiency especially in preventing lung metastases in CX3CL1 overexpressing cancer cells. However, TMI-1 did not further enhance the trastuzumab treatment efficacy.

Automated summary

In HER2-positive breast cancer patients, CX3CL1 may predict the response to trastuzumab therapy. Overexpression of CX3CL1 enhances the efficacy of trastuzumab treatment, but shedding inhibitors do not enhance the treatment effect. Further investigation is warranted in a large cohort of patients.