Follicular lymphoma and the microenvironment

In this issue of Blood, Byers and colleagues validate the role of immune signatures for prognosis in follicular lymphoma by applying RT-PCR.

Gene-expression profiling has provided a powerful means for the identification of novel prognostic factors in malignancies. However, lack of widespread availability, challenging data analysis, and high cost have been barriers to the adoption of microarrays in routine clinical use. Application of reverse transcription–polymerase chain reaction (RT-PCR) presents a potential solution to these difficulties by focusing on a subset of genes with high predictive ability.

Our work¹  and that of others^2,3  has uncovered a strong role for immune signatures in the pathogenesis and progression of follicular lymphoma. Two immune signatures, one reflecting expression from T cells and the other reflecting expression from macrophages, have been shown to be associated with survival. The current study validates those findings and extends them by providing a valuable clinical tool that can be applied at the time of diagnosis.

The nature of immune signatures in follicular lymphoma clearly deserves further exploration. The current study suggests that simply the number of T cells has a strong influence on limiting disease progression. These T cells might represent regulatory T cells described previously.³  The T-cell signature could also signify the degree to which malignant B cells are able to interact normally with T cells. When that ability is lost, malignant B cells proliferate and fewer T cells are seen in the tumor field.

The number of macrophages in the biopsy has been shown to be associated with worse survival in patients with follicular lymphoma.⁴  The present study confirms those findings. Tumor-associated macrophages have been described in other malignancies as being associated with poorer survival.⁵  In addition to their immune function, macrophages mediate tissue repair and wound healing by playing a key role in epithelial migration, matrix modeling, and angiogenesis. The same functions are also important in the progression of tumors. The association between high numbers of macrophages and poor prognosis suggests that the normal functions of macrophages may be subverted by malignancies in a way that promotes tumor progression and metastasis.

A fundamental assumption underlies all the studies that have explored molecular markers of prognosis in patients with follicular lymphoma: treatment does not affect survival. There is growing evidence that suggests a survival advantage for using rituximab in combination with chemotherapy. The impact of rituximab on expression of immune signatures and their prognostic value deserves further study.

This caveat aside, the study is valuable from 2 perspectives. First, it provides a useful method for the clinical translation of gene-expression profiling results using RT-PCR, which is relatively low in cost and widely available. Second, it provides a practical means to prognosticate the course of disease, in addition to the follicular lymphoma international prognostic index and other clinical variables of outcome, for risk stratification in clinical trials.