Immune Infiltration Assessment Promising to Predict Early Progression of Follicular Lymphoma

Expression of programmed death ligand 2 (PD-L2) may be a sensitive and specific marker to help identify patients with follicular lymphoma who are at risk for progression of disease within 24 months, according to a study published in Journal of Clinical Oncology.

“We have found that expression of immune checkpoint and immune effector molecules showed distinct clustering of follicular lymphoma samples, characterized by either high or low immune infiltration, regardless of their categorization as an immune effector immune checkpoint, or macrophage molecule,” wrote Joshua W.D. Tobin, MD, of University of Queensland, Australia, and colleagues. “Low PD-L2 was the most sensitive/specific immune molecule to segregate patients into those with or without a combined end point of progression, relapse, transformation, or death.”

Tobin and colleagues conducted the study to determine if low levels of immune infiltration were associated with inferior outcomes among patients with follicular lymphoma-a relationship seen in solid tumors. They conducted digital gene expression using a custom code set of five immune effectors, six immune checkpoints, and one macrophage. This analysis was first done in a discovery cohort of 132 patients with early or advanced follicular lymphoma, and then validated in two independent cohorts of patients with advanced disease requiring systemic treatment.

Of the molecules examined, low PD-L2 was the most sensitive and specific marker. Using this marker, Tobin and colleagues separated patient samples into those with high PD-L2 (immune infiltration high) biopsies and low PD-L2 (immune infiltration low). Immune infiltration high tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. 

The group of patients with immune infiltration low tissue was enriched with patients with progression of disease within 24 months (odds ratio [OR]=4.32; P=.001) in the discovery cohort. This was also true in the validation cohorts treated with rituximab plus cyclophosphamide, vincristine, and prednisone (OR=2.95, P=.011) and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (OR=7.09, P=.011).

“Our data indicate that patients with biopsies showing reduced immune infiltration are more likely to experience POD24 events. Although specificity was high, this was at the expense of sensitivity, which indicates that immune infiltration fails to capture a subset of patients who will develop POD24,” the researchers wrote. “This makes it a valuable predictor in certain clinical situations-for example, when testing poorly tolerated intensive regimens-but with the proviso that some patients who might potentially benefit from treatment intensification will be missed.”

Finally, the researchers found no difference in the frequency of mutated genes known to be commonly mutated in follicular lymphoma, “indicating that the degree of immune infiltration is capturing aspects of follicular lymphoma biology that are distinct from its mutational profile”.