Walter and Eliza Hall Institute
Preclinical research indicates that immune cells undergo daily, spontaneous changes that could lead to diffuse large B-cell lymphoma (DLBCL), if not for the diligent surveillance of the immune system.
Experiments in mice revealed that T cells are responsible for eliminating potentially cancerous B cells in their early stages, before they develop into DLBCL.
This immune surveillance may account for what the researchers call the “surprising rarity” of DLBCL in humans, given how often these spontaneous changes occur.
The team believes their discovery could eventually help physicians identify patients at high risk of developing DLBCL, thereby enabling preventative treatment.
Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research in Victoria, Australia, and his colleagues conducted this research and recounted their findings in Nature Medicine.
The researchers knew that many DLBCL cases are characterized by deregulated expression of the oncogene BCL6 or loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1).
But mice with mutations in either gene infrequently develop lymphoma, and, if they do, the process is slow. The same is true for humans with BCL6 mutations.
To investigate this phenomenon, the team conducted experiments in mice. The results showed that T cells prevent lymphoma development caused by Blimp1 deficiency or overexpression of Bcl6. But impairing T-cell control removed this protection.
“[W]e ‘disabled’ the T cells to suppress the immune system and, to our surprise, found that lymphoma developed in a matter of weeks, where it would normally take years,” Dr Kallies said.
The researchers also found that the DLBCL-like disease the mice developed could be eliminated by polyclonal CD8+ T cells. But deletion of the B-lymphoma cells was dependent upon the T-cell receptor, co-stimulation via CD28, and expression of the Fas ligand.
These results suggest that malignant transformation of mature B cells—in mice and perhaps in humans—is only possible when T-cell-mediated tumor surveillance is disabled.
“Each and every one of us has spontaneous mutations in our immune B cells that occur as a result of their normal function,” Dr Kallies said. “It is then somewhat of a paradox that B-cell lymphoma is not more common in the population.”
“Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle and proves that immune surveillance is essential to preventing the development of this blood cancer.”
Study author David Tarlinton, PhD, also of the Walter and Eliza Hall Institute, said this research could be used to help scientists identify pre-cancerous cells in the initial stages of their development, thereby enabling early intervention for patients at risk of developing DLBCL.
“In the majority of patients, the first sign that something is wrong is finding an established tumor, which, in many cases, is difficult to treat,” he noted.
“Now that we know B-cell lymphoma is suppressed by the immune system, we could use this information to develop a diagnostic test that identifies people in early stages of this disease, before tumors develop and they progress to cancer. There are already therapies that could remove these aberrant B cells in at-risk patients, so once a test is developed, it can be rapidly moved towards clinical use.”
