Two-photon image of a tumor (green) with blood vessels and monocytes (red). Image courtesy of the FMI
Sometimes in cancer, an immune response isn’t part of the solution. It’s part of the problem.
Example: Breast cancer and many other solid tumors can hijack macrophages, so that these enforcers of the innate immune system don’t chomp their way through the mutated cells as you might expect. Instead tumors may reprogram macrophages to release factors that help the rogue cells live long and prosper. In fact, the level of the macrophage infiltration correlates with disease progression in breast cancer.
Several labs are trying to block this tide of turncoats. One popular molecular target is CCL2, a chemokine released by breast cancer cells that helps the tumor recruit monocytes—which differentiate into macrophages—from the bone marrow.
And indeed, scientists from the Friedrich Miescher Institute for Biomedical Research (FMI) and Novartis Institutes for BioMedical Research (NIBR) have shown that neutralizing CCL2 in mice bearing mammary tumors not only prevents the tumors from recruiting monocytes but slows the process of metastasis both in the primary tumor and at metastatic sites.
So far so good.
But when the researchers continued to observe their mouse cohorts after stopping CCL2 neutralization, they got an alarming surprise—the treated mice were dying more quickly than the control mice.
That finding raises large warning flags for drugs aiming to blockade the recruitment of monocytes into breast tumors, notes Mohamed Bentires-Alj, a group leader at FMI in Basel, Switzerland and senior author of a recent Nature paper about the study.
Analysis soon made clear why the treated mice were dropping off so quickly. “When we stopped the treatment, the monocytes that were held back in the bone marrow were released and there was an overshoot of metastasis, which caused the death of the animals,” Bentires-Alj explains.
Co-lead authors Laura Bonapace and Marie-May Coissieux then found that when macrophages appeared in metastatic tumors in the lungs, interleukin IL-6 levels increased. This in turn boosted expression of the growth factor VEGF-A, which supports the formation of blood vessels. Bathed in all the blood they could use, the metastases grew huge and killed the mice, Bentires-Alj says.
On the bright side, the researchers demonstrated that damage from this flood of monocytes can be held back by inhibition of IL-6 or VEGF-A.
Their work drew on a remarkable imaging technology using a multiphoton microscope that helped to clarify the process of metastasis. Developed together with Tobias Junt, an investigator in Autoimmunity, Transplantation and Inflammation at NIBR in Basel, the microscope was customized to look at the interactions between tumors and their surrounding microenvironments in living mice (as described in this “If You Don’t Look, You Don’t See” 2012 paper). This was the starting point of a very fruitful ongoing collaboration and friendship between the two labs, Bentires-Alj says.
Overall, the study suggests extreme caution for the use of anti-CCL2 agents, and for other experimental cancer treatments that aim to suppress the migration of macrophages or other cells.
“Any tumor immunotherapy that only sequesters immune cells away from the tumor and that does not permanently reprogram the tissue microenvironment or directly kill tumor cells may bear a similar risk of lethal rebound,” as theNature paper points out.
Bentires-Alj adds that the research should raise awareness of the importance of strict monitoring of disease and treatment over time, not just in the clinic but in the animal lab.
“This is a change of culture,” he says. “Shrinking the tumor is good stuff but whether you can increase survival is what matters at the end of the day.”