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T Cell Receptor Sequencing IDs Aggressive Lymphoma Subtype

NEW YORK (GenomeWeb) – A team from Dana-Farber Cancer Institute, Brigham and Women's Cancer Center, Harvard Medical School, and Adaptive Biotechnologies has identified characteristic T cell receptor beta gene patterns coinciding with particularly aggressive cases of mycosis fungoides (MF), a form of cutaneous T cell lymphoma (CTCL) affecting CD4+ T cells with alpha and beta T cell receptor subunits.

The researchers used high-throughput T cell receptor beta gene (TCRB) sequencing to assess skin biopsy samples from 208 individuals with CTCL, including 177 MF cases. During a 15-year observational study, they found that increasing tumor clone frequency in the CTCL skin lesion biopsies typically coincided with poorer progression-free survival and overall survival times, particularly for individuals with MF.

Similar ties between tumor clone frequency and patient outcome turned up when the team tested another set of samples from 101 individuals with MF or other forms of CTCL, highlighting early-stage tumor clone frequency of the TCRB gene as an independent predictor of patient outcomes. The findings were published online today in Science Translational Medicine.

"While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease, and treat them in a more aggressive fashion with the intent to better manage, and ideally cure, their cancer," co-senior author Thomas Kupper, dermatology chair at Brigham and Women's Hospital, said in a statement.

More than four-fifths of MF cases are indolent and progression-free, the team noted, but the remaining cases can become highly aggressive and life threatening, highlighting a need for strategies to detect these risky MF cases. And while some clinical features have come to the forefront for finding aggressive disease in the later stages of MF, the hunt is on for early-stage markers of aggressiveness.

Following from a 2015 Science Translational Medicine study by members of the same team that pointed to TCR gene sequencing as a means of detecting malignant T cells, the authors reasoned that TCR clonality might also offer clues to CTCL patient outcomes.

"Because each T cell clone has a unique TCR complementarity-determining region 3 (CDR3) sequence," they wrote, "DNA sequencing allows the precise identification and absolute quantification of both malignant and benign T cell clones in CTCL."

For the discovery stage of their study, the researchers focused on "lesional" biopsy samples from 208 CTCL patients participating in a longitudinal study at Dana-Farber — a set that included characteristic inflammatory skin patch or skin plaque biospies from the 177 individuals with the MF form of disease.

Collaborators at Adaptive Biotechnologies used that firm's ImmunoSEQ platform to profile the CDR3 region of the TCRB gene, identifying a decline in progression-free and overall survival time in cases marked by more than 25 percent tumor clone frequency in early-stage biopsy samples. The team replicated the result in 101 more individuals with CTCL, where tumor clone frequency and outcomes were significantly linked to progression-free survival in the 87 individuals with MF.

The researchers subsequently limited their analyses to MF disease, demonstrating that their proposed tumor clone frequency test could predict disease progression and overall survival independent from other risk factors such as disease stage. A tumor clone frequency surpassing 25 percent had a positive predictive value of 92 percent for disease progression or death after five years, they reported.

"The [tumor clone frequency] of [more than 25 percent] in the skin was a stronger predictor of progression than any other established prognostic factor," Kupper and co-authors wrote, noting that tumor clone frequency "may accurately predict disease progression in early-stage MF."

Meanwhile, when the researchers considered gene expression for dozens of previously proposed CTCL biomarkers in 157 individuals with early- or advanced-stage MF, or another form of CTCL called Sézary syndrome, they found that high tumor clone frequency tended to coincide with increased expression for genes in the JAK-STAT and TCR signaling pathways, providing additional clues to the hallmarks of aggressive disease.

Likewise, their exome sequencing analysis of skin T cell and matched normal blood samples from 19 individuals with MF suggested that somatic mutations tend to rise in skin samples from those with prognostically poor tumor clone frequency profiles.

"Our gene expression data suggest that therapeutic inhibition of TCR signaling in CTCL may be a useful strategy, although other pathways might be involved in CTCL cell survival," the authors wrote, adding that "the role of immunomodulatory therapies in this subset of high-risk patients should be assessed."