Abstract
The immune system and tumor microenvironment play a decisive role in tumor progression. We developed a novel model to better understand tumor progression and interaction with immune cells and the cellular components. We grew 393 P non-metastatic and 344SQ metastatic murine cells in an acellular metastatic lung cancer model, where both cell lines formed circulating tumor cells (CTC) and metastatic lesions. When the CTC from this model were placed in the tail vein of nu/nu mice, both cell lines formed metastatic lesions. However, in syngeneic immune-competent mice, the CTC from the non-metastatic cell line did not metastasize while the CTC from the metastatic cell line metastasized. When we placed the activated immune cells in the cellular lung model, it decreased CTC and metastatic lesion formation for the non-metastatic cell line while it had no impact on metastatic cell line. The metastatic cell line had a significant increase in expression of programmed death-ligand 1 (PDL-1) compared to the non-metastatic cell line in the model. Overall, the immune cells showed an impact on viability of CTC for cell lines with a decreased expression of PDL-1 that leads to decreased metastatic lesion formation. Further studies are needed to understand the subtype of immune cells and mechanism of decreased CTC viability and metastasis inhibition.
Highlights
Tumor cells grow by developing multiple immunosuppressive mechanisms to prevent immune cells from killing the abnormal cells
Image of metastatic 344SQ cells grown on the acellular 4D model (D), hematoxylin and eosin (H&E) of the primary tumor (10×, E) and H&E of the metastatic lesion (40×, F). (G) Graph shows no significant difference in metastatic lesion formation in high power field (HPF) between 393P and 344SQ cells on acellular 4D model on day 15 (p = 0.5)
These circulating tumor cells (CTC) were obtained by collecting cell culture media that circulated in lung for 24 hours in the bioreactor through the vasculature of ex vivo 4D lung model, spinning them at 500 g for 5 minutes, discarding supernatant and reconstituting the pellet with 1 ml of fresh media
Summary
Tumor cells grow by developing multiple immunosuppressive mechanisms to prevent immune cells from killing the abnormal cells. We have developed a 4D lung cancer model that mimics the metastatic process and allows us to isolate tumor cells at different phases of tumor progression, namely at the primary tumor site, circulating tumor cells (CTC), and metastatic lesions[13,14,15]. Using this model, we discovered the mechanism of immune cell interaction with tumor cells and its impact on metastasis. Our study shows that immune cells decrease the CTC viability that leads to decreased metastasis for certain cell lines
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