Rather than stimulating immune cells to more effectively battlecancerous tumors, treatment with the protein interleukin-12 (IL-12)has the opposite effect, driving these intracellular fighters toexhaustion, a Mayo Clinic study has found. The findings appear inthe Journal of Clinical Investigation. The study helps explain the negative results of clinical trialstesting the treatment’s ability to ramp up the body’s naturalimmune response to destroy cancer cells. The study also demonstrates that the same “T cellexhaustion” that plagues specialized immune cells during chronicviral infections also affects cells fighting long bouts of cancer.
The results suggest a change in therapeutic tactics for lymphomas and other cancers by dampening, rather than fueling, the effectsof cell-signaling molecules such as IL-12. The study focused on a type of cancer called Follicular B-cellnon-Hodgkin’s lymphoma (FL), the second most frequent type ofnon-Hodgkin’s lymphoma. Previously, senior author Stephen Ansell,M.D., Ph.D., a Mayo Clinic hematologist, had shown that tumorsbiopsied from patients with FL and other similar cancers are a50-50 mixture of cancer cells and immune cells. Although thoseimmune cells are genetically programmed to kill cancer, instead,they seemed content to cohabitate with their deadly neighbors. Dr.Ansell wondered if a phenomenon known as T cell exhaustion may bethe cause.
The study findings suggest it is. “It is like beating a dead horse,” says Dr. Ansell. “Our studysuggests that many immunotherapy approaches are futile, becausethese cells are already past the point where they can do their jobof targeting and killing malignant cells. Before we can stimulatethe immune system, we have to reverse this state of exhaustion sothe body’s T cells can get back to work.” T cell exhaustion was discovered a few years ago in the context ofchronic viral infections such as cytomegalovirus (CMV), hepatitis and HIV. High Lumen Led Bulbs
Researchers found that constant unrelenting combat with theseviruses caused a key contingent of the immune response, known as Tcells, to wear out. Even when artificially stimulated, theseexhausted cells were unable to proliferate, recruit other membersof the immune army, or kill enemy cells. In addition, these T cellsbegan to carry cellular marks of exhaustion, most notably the cellsurface proteins PD1 and Tim-3. In this study, Dr. Ansell and his colleagues tested whetherexposing isolated human T cells to IL-12 would induce T cellexhaustion. China Outdoor Led Spotlights
They found that treatment with IL-12 brought the Tim-3marker of exhaustion to the cell surface. When they triedexperimentally to stimulate those immune cells into action, theydiscovered that the T cells couldn’t proliferate and couldn’t makethe immune system signaling molecules known as cytokines. “We think that IL-12 is useful in the short term, but detrimentalin the long term,” Dr. Ansell says. “Almost like pouring gasolineon a campfire: You get a really big blaze, but then it all burnsdown to nothing.” The researchers found that the more cells marked with Tim-3 in agiven tumor, the worse the patient’s prognosis. China Led Downlight
They also showedthat by blocking Tim-3 they could return the T cells to normalfunction. “Once we’ve worked out all factors that are contributing toexhaustion, the next step will be figuring out which of them can werealistically reverse, particularly in the context of patients,”Dr. Ansell says. “Some of these cytokines have a critical role inthe body, and we wouldn’t want to reverse good effects along withthe bad.” Additional References Citations.