Reprogramming Tumor Cells

Tumor-associated macrophages (TAMs) are the most abundant immune cells in tumors. Extremely adaptable, they shift their function according to the microenvironment: They can be both pro- and anti-tumor. In most solid tumors, they’re immunosuppressive and pro-growth. This makes them a “remarkably promising” target in immuno-oncology, according to researchers in the innate immunity group at the Germans Trias i Pujol Research Institute in Badalona, Spain, outside Barcelona. The key, they say, is to reprogram TAMs. Their study, published in EBioMedicine, suggests that doing so could change the prospects of millions of lung cancer patients.

Maria Rosa Sarrias, Ph.D., iof Germans Trias i Pujol Research Institute in Spain, rled esearch that involved manipulating the tumor microenviroment.

Led by Maria Rosa Sarrias, Ph.D., the researchers had found in an earlier study that CD5L, a glycoprotein, drove cells toward a polarization similar to that induced by IL10, and that IL10-activated macrophages in vitro overexpressed CD5L.

In the current study, they found that CD5L was a “key player” in macrophage responses in the context of cancer. They determined that CD5L blockade reverted interleukin (IL)-10-induced macrophage activation. “Interestingly,” they note, blocking CD5L also inhibited CD5L expression, suggesting that this protein undergoes a positive feedback of transcriptional regulation. Their observations point to a positive feedback loop between CD5L expression and the maintenance of the immunosuppressive phenotype. Therefore, they concluded that CD5L is a TAM marker induced by factors secreted by cancer cells. High TAM CD5L protein in advanced lung cancer supports the notion that CD5L contributes to a poor prognosis.

To explore the therapeutic potential of targeting CD5L, the team generated a CD5L-blocking monoclonal antibody, which they named RImAb. They describe RImAb as a modulator of several hallmarks, namely vascularity, apoptosis and epithelial-mesenchymal transition factors. Administered in a mouse model of lung cancer, the antibody reduced tumor growth, reprogrammed TAMs and shifted the tumor microenvironment to be “less tumor permissive.”

The RImAb-treated group of mice showed an increase in neutrophils, which the researchers note play “important and conflicting roles in cancer development.”In their study, the expression of myeloperoxidase, a marker of neutrophil activation, negatively correlated with tumor volume, suggesting that neutrophil infiltration contributes to tumor control by RImAb. The RImAb-associated increase in neutrophils was also in line with higher levels of tumor GM-CSF, a chemoattractant for neutrophils that may have antitumor activity.In contrast, the researchers observed diminished levels of GM-CSF in the serum of RImAb-treated animals. Higher GM-CSF serum levels, they point out, are considered a marker of adverse clinical outcome, especially in patients with non-small cell lung cancer.

The results “open the door to a new line of treatment for lung cancer patients,” Sarrias said in an interview, “with the potential to be applied to other solid tumors.”