One potent, immune-based treatment for cancer is total body irradiation (TBI). This approach first depletes the body of the population of immune cells known as lymphocytes and then involves the adoptive transfer of tumor-specific T cells to the patient. Lymphodepletion has previously been shown to improve the ability of tumor-specific T cells to cause tumor regression.
In a study appearing online on July 26 in advance of publication in the August print issue of the Journal of Clinical Investigation, Nicholas Restifo and colleagues from the National Cancer Institute show that, in mice, lymphodepletion does not fully account for the tumor regression observed following TBI. They show that a disruption of the population of bacteria that normally reside in the gut without causing disease also plays a role in the effectiveness of this therapeutic approach for cancer.
A specific population of bacteria present in our gut is crucial to our health. However, some treatments for cancer, particularly those that deplete the body’s immune cells, have high potential to disrupt the natural balance between our bodies and these commensal microorganisms, causing disease. Restifo and colleagues subjected mice genetically deficient in lymphocytes to TBI and found that, like TBI-treated mice with intact lymphocytes, TBI was still able to positively augment the function of adoptively transferred tumor-specific CD8+ T cells and cause tumor regression. This surprising result indicated that another mechanism for the efficacy of TBI also exists. They found that in these mutant, irradiated mice the lining of their gut was injured, allowing the passage of commensal bacteria from the gut to the lymph nodes, where the immune response to their presence increased the activation of tumor-specific CD8+ T cells and resulted in tumor regression.
This effect was found to involve toll-like receptor 4. Conversely, a reduction in the number of host microorganisms by the use of antibiotics reduced the beneficial effects of TBI on tumor regression in these animals. In summary, the results of the study demonstrate that the disruption of the host/microorganism balance by TBI and the resulting transient bacterial infection is a key mechanism driving the increased reactivity of tumor-specific CD8+ T cells and subsequent tumor regression in mice.
TITLE: Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling