Insights on Lung Micro-Environment Explain Why Cancer Spreads to the Lungs

August 25, 2016
Process of lung metastasis

COLUMBUS, Ohio – The same mechanisms that that prevent people from having an inflammatory response to harmless environmental exposures in day-to-day life could also all allow rogue cancer cells to spread to the lungs, according to new research from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Researchers have discovered and described how the lung’s unique underlying immune environment enables cancer to readily spread to the organ. They report their findings online ahead of print in the scientific journal, Cell, on Aug. 25, 2016.

Cancer cells must break through normal immune defenses in order to spread to other parts of the body. Little is known, however, about the mechanisms that lead to cancer’s spread to the lungs. Nearly 90 percent of cancer deaths occur when cancer spreads to a different part of the body –presenting a major obstacle to curative treatment.  The lungs are a common site of metastasis for primary bladder, breast, colon, kidney, melanoma, ovary, pancreas, bone, rectal, stomach, thyroid, uterine and lung cancer.

In this new study, researchers describe how oxygen functions as an immune system checkpoint to create an environment that enables cancer’s spread to the lung more easily.

“Every time we take a breath, we bring things into our lungs that could produce a pretty dramatic and potentially harmful immune response – but the majority of the time they don’t because in a normal, healthy state our immune systems are set up to accommodate for this,” explains David Clever, PhD, first author of the manuscript and a current medical student at Ohio State. Clever completed this research under the mentorship of Nicholas Restifo, MD, of National Cancer Institute (NCI) during the doctoral portion of his Medical Scientist Training Program.

“The same ‘normal’ mechanisms put in place to suppress immune responses against harmless material taken into the body during the act of breathing can also suppress immune responses to the colonizing cancer cells that lead to metastatic tumors in the lungs. This creates an immunologically favorable niche – meaning the environment is prime for cancer cells to slip through the immune system’s defenses, thrive and grow in the lungs.”

Specifically, the team discovered that certain oxygen-sensing proteins (PHD cells) function to limit inflammation by T cells, a type of immune cell capable of killing cancer cells.  In the highly oxygenated lung microenvironment the oxygen-sensing PHD proteins limit immune responses against cancer cells which opens the lung up as a a fertile ground for metastasis.

Researchers found that by blocking the PHD proteins -- using either pharmacologic agents or mice bred to have the PHD proteins “knocked-out” of their T cells -- they could enhance T-cell responses against cancer and limit metastasis to the lung.

These results contribute a new immunological basis for the predisposition of many cancers to metastasize to the lung that could help scientists develop new therapies to prevent the spread of cancer to the lungs. 

“Adoptive cell transfer immunotherapy provides a unique opportunity for manipulation of a patient’s own T cells out of the body,” said Restifo. “Although our finding is in mice, we are eager to test whether disruption of the oxygen sensing machinery in T cells -- with drugs, genetics, or regulation of environmental oxygen -- will enhance the efficacy of T-cell mediated immune therapies for cancer in humans.”     

The study was funded by NCI and National Institute of Allergy and Infectious Diseases (NIAID) and with charitable gifts from Li Jinyuan, The Tiens Charitable Foundation and The Milstein Family Foundation. Additional support was provided by The Wellcome Trust/Royal Society and The UK Biotechnology and Biological Sciences Research Council.

Collaborators in this study include Rahul Roychoudhuri, Madhusudhanan Sukumar,  Christopher Klebanoff, Robert Eli, Zhiya Yu, Jenny Pan, Douglas Palmer,  and Luca Gattinoni of NCI; Michael Constantinides, Michael Askenase, Heather Hickman and Yasmine Belkaid of NIAD; and Anthony Phan, John Goulding and Ananda Goldrath of the University of California.

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About the OSUCCC – James

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 46 National Cancer Institute-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs. As the cancer program’s 308-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care.

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