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

Bayer Thrombosis Research Award 2019 goes to Dr. C…

The fourth winner of the Bayer Thrombosis Research Award has been chosen. The Scientific Committee of the Bayer Science & Education Foundation awarded the EUR 30,000 priz...

Roche enters into definitive merger agreement to a…

Roche (SIX: RO, ROG; OTCQX: RHHBY) and Spark Therapeutics, Inc. (NASDAQ: ONCE) have entered into a definitive merger agreement for Roche to fully acquire Spark Therapeuti...

Brilinta’s Phase III THEMIS trial met primary endp…

The Phase III THEMIS trial met its primary endpoint and demonstrated that Brilinta (ticagrelor), taken in conjunction with aspirin, showed a statistically-significant red...

Protein content as a marker for response to therap…

Brain tumors vary widely in how they respond to treatment. However, early assessment of therapy response is essential in order to choose the best possible treatment for t...

Jury upholds Amgen's patents on Repatha® (evolocum…

Amgen (NASDAQ:AMGN) announced that a Delaware jury delivered a verdict in Amgen's favor upholding the validity of two Amgen patents related to PCSK9 antibodies. These pat...

Artificial lung cancer tissue could help find new …

A 3D hydrogel created by researchers in U of T Engineering Professor Molly Shoichet's lab is helping University of Ottawa researchers to quickly screen hundreds of potent...

Could medical marijuana help grandma and grandpa w…

Medical marijuana may bring relief to older people who have symptoms like pain, sleep disorders or anxiety due to chronic conditions including amyotrophic lateral scleros...

New treatment offers potentially promising results…

A pioneering clinical trials program that delivered an experimental treatment directly to the brain offers hope that it may be possible to restore the cells damaged in Pa...

Amgen, Cytokinetics and Servier announce start of …

Amgen (NASDAQ: AMGN), Cytokinetics, Incorporated (NASDAQ: CYTK) and Servier today announced that METEORIC-HF (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecar...

Could blockchain ensure integrity of clinical tria…

UC San Francisco researchers have created a proof-of-concept method for ensuring the integrity of clinical trials data with blockchain. The system creates an immutable au...

Novartis data confirm rapid response and high effi…

Novartis announced today new data in 441 Chinese patients with moderate to severe plaque psoriasis from a Phase III study investigating the efficacy and safety of Cosenty...

Abbott and Novo Nordisk enter partnership to provi…

Abbott and Novo Nordisk today announced a non-exclusive partnership that will integrate insulin dose data from Novo Nordisk pre-filled and durable connected pens directly...