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Monday, September 19, 2011
Powering NK Cells: Finding A Break in Immune Surveillance
Double immunofluorescence for nestin (pink) and the endothelial marker CD34 (green) with EGFR fluorescence in situ hybridization (red) confirms expression of nestin in endothelial cells and in glioblastoma cells of patients treated with cediranib. Courtesy of (Co-Chairperson, Rakesh Jain’s lab): di Tomaso et al. Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape. Cancer Res; 71(1): 19-28, January 1, 2011.
 

One of the great things about my job is that I get to attend a substantial number of scientific meetings. And some days I hear talks that leave my imagination running in high gear. Thursday, at the AACR Frontiers in Basic Science Conference in San Francisco, was one of those days.

 Lewis Lanier, PhD, American Cancer Society Research Professor and Chair of Microbiology & Immunology at the University of California at San Francisco, described the role of natural killer (NK) cells in immune defense against tumor cells and how the system breaks down in cancer patients.

 

The work makes me think of James Allison’s seminal insights into the regulation of T cells, which ultimately led to ipilimumab and other anti-CTLA-4 antibodies. In fact, Dr. Allison, who was in the audience for Dr. Lanier’s presentation, said it is not unrealistic to think Dr. Lanier’s work will eventually lead to novel immunotherapies, somewhat analogous to ipilimumab.

 

It has been known for some time that NK cells isolated from the blood of healthy adults will attack and kill tumor cells in culture. However, NK cells isolated from the blood of cancer patients have lost that ability and largely ignore the aberrant cells.

 

Remarkably, Dr. Lanier and collaborators --Courtney Crane, PhD, a postdoctoral fellow, and Andrew T. Parsa MD, PhD, Associate Professor of Neurological Surgery at UCSF -- found that surgically removing glioblastoma tumors from patients restored their NK cells’ anti-tumor activity. In other words, removing the tumor causes a systemic shift that re-establishes the ability of NK cells to target cancer cells, even when the NK cells are in the blood stream and nowhere near the tumor site.

 

Previous reports suggested that tumors suppressed NK cells by releasing soluble antigens that saturated key receptors on the surface of NK cells, called NK2GD receptors. However, Dr. Lanier’s group and other research groups have not been able to replicate those findings, he reported yesterday.

 

Instead, his team has found that the presence of a tumor somewhere in the body triggers expression of NK2GD ligands ULBP1 and MICA/B on the surface of peripheral blood mononuclear cells (PBMCs). That means the NK cells are constantly bumping into NK2GD ligands in the blood stream. The frequent ligand-receptor binding causes internalization of the NK2GD cell surface receptor and degranulation of the NK cells -- effectively suppressing anti-tumor NK cell activity well before the immune cells ever see the tumor.

 

Moreover, the pattern of suppression and reactivation after surgical resection holds up for numerous types of cancer, including liver, prostate, and breast. That suggests that like Dr. Allison’s work on T cell regulation, the UCSF team has uncovered a common immunological mechanism.

 

The researchers haven’t yet figured out exactly what triggers PBMCs to express NK2GD ligands, but they are getting close.

 

So far, they know the factor is secreted by tumors (or tumor cells grown in culture), that it is degraded in heat and therefore likely to be a protein, and that it is small, ) between 10 and 50 kDa in molecular weight. But that is as close as they’ve gotten.

 

Dr. Crane, though, has grown enormous quantities of glioblastoma cells and is using mass spectrometry and purification columns to isolate and identify the critical factor.

 

I found the work exciting simply from a biology standpoint (Who expected that tumor-NK link to be so sneaky and elegant?) and because it has potential clinical implications.

 

If all goes as hypothesized, treating patients with an antibody against the soluble factor could restore the ability of their NK cells to control tumor growth. Additionally, Dr. Lanier noted that the shift in PBMC gene expression might be a biomarker for recurrent disease, well before a tumor is visible by standard imaging techniques.

 

Dr. Lanier’s talk at this meeting wasn’t taped, but here is a link to an award lecture he gave in February at his home institution.

 

(Dr. Lanier reports that he and his institution have potential financial conflicts related to his NK cell work.)

 

About the Author

Rabiya S. Tuma, PhD
RABIYA S. TUMA, PHD, a Contributing Writer for Oncology Times, is an award winning journalist and a regular contributor to The Economist, and the Journal of the National Cancer Institute. Her work has appeared in a variety of publications including CR Magazine, Yoga + Joyful Living, O The Oprah Magazine, HHMI Bulletin, and the New York Times. Prior to launching her writing career, Rabiya earned her doctorate at the University of Washington and Fred Hutchinson Cancer Research Center and worked at a biotechnology firm in Eugene, Oregon. And though she traded a lab bench for a computer, she remains fascinated with the work that takes basic science into the clinic.

Her OT blog was recognized this year by the American Society of Healthcare Publication Editors (ASHPE) with a bronze award in the category of Best Blog.