Stopping cancer from recruiting immune system double agents

Cancerous tumors trick myeloid cells, an important part of the immune system, into perceiving them as a damaged part of the body; the tumors actually put myeloid cells to work helping them grow and metastasize (spread). A research team co-led by scientists at Rush University Medical Center have discovered a potential therapy that can disrupt this recruitment and abnormal function of myeloid cells in laboratory mice. The findings of their latest study were published on Dec. 19 in Nature Communications.

Myeloid cells are a type of white blood cell that kills invaders like bacteria and cancer. "In the cancer context, myeloid cells promote tumor growth and suppress the activity of T cells," says Vineet Gupta, PhD, professor and vice chairperson for research and innovation in the Department of Internal Medicine at Rush Medical College.

Gupta and Judith Varner, PhD, of the Moores Cancer Center at the University of California at San Diego (UCSD) in California, were co-senior corresponding authors on the study. Samia Khan, PhD, a post-doctoral fellow in Gupta's lab; and Michael Schmid, PhD, and Megan Kaneda, PhD, with UCSD, were co-first authors.

Cancer recruit harmful myeloid cells, while suppressing helpful ones

Gupta's research focuses in general on integrins, a type of protein that are cellular receptors and regulate a number of biological processes. In this study, investigators looked at the integrin CD11b, which I present on myeloid cells and normally helps myeloid cell migration and its ability to fight disease.

Here, the researchers found that CD11b promotes development of myeloid cells into one sub-type, the M1 macrophage, that functions appropriately to suppress tumor growth. However, the tumors often suppress CD11b activity that results in development of the myeloid cells into a different type of cell, the M2 macrophage. These cells actually ward off T cells, which are vital to fighting disease, and M2s also secrete growth factors and promote the development of new blood vessels that allow cancer to grow and metastasize.

In previous research, agents developed to activate T cells have been "extremely effective in controlling tumor growth," Gupta says, but that approach, known as immunotherapy, has not resulted in a universal treatment for cancer. The hunt goes on.

Study found that CD11b is critical in regulating myeloid cells

In this study, the team explored how modifying the activity of CD11b affects myeloid cell behavior in the presence of cancer and if that could be used as a novel strategy to treat cancers. Using a small molecule discovered in the Gupta laboratory, Leukadherin-1 (LA-1), which in the body activates CD11b, the researchers developed a therapy that can boost the function of CD11b to promote the disease-fighting M1 type of myeloid cells, helping create a microenvironment at the tumor site where T cells can enter and attack the cancer.

The study used two types of genetically altered mice. One set of experiments was done with otherwise normal mice that lacked CD11b. Transplanted tumors grew much larger in those mice as compared to the tumors in wild-type (normal) mice, suggesting that CD11b restrains tumor growth.

Exploring further the reason for this difference, the team found that CD11b plays a critical role in regulating the polarization of myeloid cells into M1 or M2 macrophages. In the absence of CD11b, most of the myeloids cells in tumors were the M2 sub-type, that help the tumor grow and spread.

Boosting CD11b activity helped reduce tumor growth

In a different experiment, the team used LA-1 to boost CD11b activity beyond its normal levels in wild-type (normal) mice, and discovered that this increase caused a significant reduction in tumor growth in treated animals. Then, to be sure that their pharmacological intervention was directly due to the effects of LA-1 on CD11b, they created a mouse with a "point mutation" (a genetic mutation at a single residue in the CD11b protein sequence) and created a situation in which CD11b was active all the time (which is usually isn't) in the genetically modified animals.

"The boost in CD11b activity in the mouse with the point mutation mimics the one imparted on CD11b in normal mice with administration of LA-1," Gupta says. "The results were the same," Gupta says. In both cases, the tumors shrank dramatically, suggesting CD11b activation as an novel target for cancer immunotherapy.

In this study, LA-1 showed a great deal of promise, although, Gupta says it will be years before a treatment based on this molecule becomes available to patients. The results are very encouraging and will continue to motivate the team to move this novel approach towards developing treatments for patients.

Michael C Schmid, Samia Q Khan, Megan M. Kaneda, Paulina Pathria, Ryan Shepard, Tiani L Louis, Sudarshan Anand, Gyunghwi Woo, Chris Leem, M Hafeez Faridi, Terese Geraghty, Anugraha Rajagopalan, Seema Gupta, Mansoor Ahmed, Roberto I Vazquez-Padron, David A Cheresh, Vineet Gupta, Judith A Varner.
Integrin CD11b activation drives anti-tumor innate immunity.
Nature Communicationsvolume 9, Article number: 5379 (2018) doi: 10.1038/s41467-018-07387-4DO.

Most Popular Now

Cancer cells are quick-change artists adapting to …

Until now, researchers have assumed that the growth of solid tumors originates from cancer stem cells characterized by specific surface markers, which develop in a fixed...

Nucala (mepolizumab) gains FDA approval for two ne…

GlaxoSmithKline (LSE/NYSE: GSK) announced that the US Food and Drug Administration (FDA) has approved two new methods for administering Nucala (mepolizumab), an autoinjec...

Cannabis use among older adults rising rapidly

Cannabis use among older adults is growing faster than any other age group but many report barriers to getting medical marijuana, a lack of communication with their docto...

Jeff Settleman, Ph.D., joins Pfizer to lead Oncolo…

Pfizer Inc. (NYSE: PFE) announced that Jeff Settleman, Ph.D., will join the company as Senior Vice President and Group Head of Oncology Research & Development, leading al...

Cleveland researchers test novel gene therapy for …

A novel gene therapy clinical trial at University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center is showing promising results, garnering funding...

Merck pioneers new effort to see MS from the insid…

Merck, a leading science and technology company, joins the global multiple sclerosis (MS) community in recognition of World MS Day, an initiative created by the Multiple ...

Full data from CAROLINA® outcome trial support lon…

Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY) announced full data from the CAROLINA® trial demonstrating that Trajenta® (linagliptin) did not increase cardio...

Bristol-Myers Squibb announces post-closing leader…

Bristol-Myers Squibb Company (NYSE:BMY) today announced the future leadership team of the combined company effective upon completion of the company’s pending merger with ...

Novartis Kisqali significantly extends life in wom…

Novartis announced statistically significant overall survival (OS) results for Kisqali in combination with endocrine therapy[1]. The Phase 3 MONALEESA-7 trial evaluated K...

Amgen joins with community oncology networks for n…

Amgen (NASDAQ: AMGN), along with leading community oncology networks, today announced the launch of Amgen Community Oncology Research Collaborators (ACORC), a new initiat...

Bayer receives U.S. FDA breakthrough therapy desig…

Bayer announced today that the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for copanlisib (Aliqopa™) for the treatment of adult patie...

Prescription drug costs steadily soar, yet price t…

After reviewing tens of millions of insurance claims for the country’s 49 most popular brand-name prescription drugs, a team from Scripps Research Translational Institute...