Killer T Cells See Cancer Driving Mutations before Turning Blind Eye

Early in tumor development, well before a tumor becomes clinically recognizable, so-called driver mutations steer cancerous cells down aberrant developmental paths, changing not only the behavior but also the appearance of the cells. And yet these altered cells would seem to escape the notice of the immune system’s killer T cells, which are supposed to detect signs of corruption and then react accordingly, by living up to the name “killer.”

Although killer T cells are known to give cancer cells a pass early in tumor development, it is unclear whether they wink at driver mutations from the start, or whether they surveil these genetic aberrations before turning a blind eye. According to new research from the Fred Hutchinson Cancer Research Center, killer T cells are vigilant at first, but soon become inattentive. This finding raises the possibility that killer T cells could regain their sense of mission, enhancing the effectiveness of immunotherapies against cancer.

The new research appeared August 9 in the journal Immunity, in an article entitled, “Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.” This article describes how preclinical cancers were studied in mice to reveal the killer T-cell response. The killer T cells, the article explained, not only recognize changes that drive cancer, they also attempt to launch an immune attack on cancerous cells.

“Early during the pre-malignant phase of tumorigenesis, TST [tumor-specific CD8⁺ T] cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors,” wrote the article’s authors. “Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state.”

The authors added that persistent antigen exposure, rather than factors associated with the tumor microenvironment, drove dysfunction. Moreover, the authors indicated that TST cell differentiation and dysfunction program exhibited features distinct from T-cell exhaustion in chronic infections.

“Our results highlight that driver mutations, which theoretically would be the most effective antigens to target because they represent the basis for a tumor behaving as a tumor, are not immunologically silent and can indeed be recognized,” said Fred Hutchinson Cancer Research Center immunologist Phil Greenberg, M.D., who led the study along with Andrea Schietinger, Ph.D., a former Fred Hutch postdoctoral research fellow who now leads an immunotherapy lab at Memorial Sloan Kettering Cancer Center.

Dr. Greenberg’s research team is now pursuing two strategies to build off their findings. These focus on:

– Defining the molecules that render the tumor-recognizing T cells dysfunctional, with the ultimate goal of disrupting those silencing molecules.

– Engineering T cells in the laboratory for eventual therapeutic use that recognizes the driver mutations but cannot be shut off by tumors.