Study develops strategy cancerous tumors disrupt development of immune response., ET HealthWorld

Houston : A method that malignant tumours use to remotely prevent the emergence of an immune response that would halt their growth has been discovered by researchers at Baylor College of Medicine and associated institutions.

The research, which was published in the journal Cell Stem Cell, demonstrated using animal models that breast cancer tumours communicate with the bone marrow, where immune cells are produced. The signals change the bone marrow’s natural milieu in such a manner that they block the body’s normal response to the tumour. Weirdly, these alterations continue for a long time after tumour removal.

The excision of the tumour can speed up the restoration of normal conditions in the bone marrow, which in turn speeds up the immune system’s recovery. The results call for more study, which might eventually result in better patient care.

“Research has shown that breast cancer can have a significant impact in the body even before it metastasizes or spreads to other organs. For instance, tumors can remotely disrupt the ecosystem inside the bone marrow, leading to an immune response that does not attack the tumor but favors its growth instead,” said corresponding author Dr Xiang H.-F. Zhang, William T. Butler, MD, Endowed Chair for Distinguished Faculty and interim director of the Lester and Sue Smith Breast Center at Baylor. “To understand how this happens, we characterized the organization of the bone marrow in breast cancer animal models before the tumor had metastasized.”

The team found that even small tumors can affect the body profoundly as they trigger multiple changes in the bone marrow.

“Breast cancer tumors promote the over production of bone marrow cells called osteoprogenitor cells, which will later contribute to the formation of new bone,” said first author Dr. Xiaoxin Hao, postdoctoral associate in the Zhang lab.

In addition, other cells, the progenitors of cells that give rise to immune cells, also grow in numbers. Importantly, these progenitors also change their typical location within the bone marrow, relocating near the osteoprogenitor cells and establishing a new cell-to-cell communication with these cells, particularly with a subset called granulocyte-monocyte progenitors (GMPs).

“We think that this osteoprogenitor-GMP communication is key, because GMPs give rise to neutrophils and monocytes, immune cells that have long been known to accumulate in some breast cancer tumor in patients and breast cancer mouse models and help promote tumor growth by suppressing the anti-tumor immune response,” Hao said.

The researchers were surprised to find that after they removed the tumor, which they considered the source of the problem, the disruption of the bone marrow did not recover immediately.

“We observed this in animal models,” Hao said. “In some patients, we have seen that even more than 40 weeks after removing the tumor, increased numbers of neutrophils remain in their blood, which is clinically relevant.”

In some cases, tumor removal is followed by immunotherapy, which relies on an intact immune system for its success. “Our findings suggest that at least in some patients the immune system is still compromised after removing the tumor, likely reducing the beneficial effects of immunotherapy,” Zhang said.

In addition, the findings have implications for metastasis. Metastasis may arise years or even decades after the tumor has been surgically removed seeded by residual cancer cells left behind after the surgery. “An immunosuppressive effect lingering after the surgery may create an environment favorable for the residual cancer cells to proliferate and metastasize,” Hao said.

The researchers also identified protein MMP-13 as an essential mediator of the crosstalk between osteoprogenitor cells and GMPs. “We showed that if we eliminate or inhibit MMP-13, we can accelerate the recovery of the immune system and restore the efficacy of immunotherapies,” Hao said.

“Our findings suggest a new modality of treatment that is very different from the current strategies. It’s not targeting the cancer cells, it’s not targeting immune T cells that attack cancer cells, it’s targeting the whole organism. It’s trying to remove a kind of shadow cast over the entire immune system,” Zhang said. “This is just the beginning of a series of studies on how tumors alter the whole body. Our findings support continuing our research on this path, and we hope it will lead to the identification of improved treatments for cancer patients.”

  • Published On May 5, 2023 at 01:05 PM IST

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