In a study reported in the Journal of Clinical Oncology, Tobin et al found that low tumor immune infiltration—indicated by low programmed cell death ligand 2 (PD-L2) expression—was associated with earlier disease progression in follicular lymphoma.

As stated by the investigators, “Understanding the immunobiology of the 15% to 30% of patients with follicular lymphoma who experience progression of disease within 24 months remains a priority. Solid tumors with low levels of intratumoral immune infiltration have inferior outcomes. It is unknown whether a similar relationship exists between progression of disease within 24 months in follicular lymphoma.”

Study Details

In the study, immune infiltration profile was investigated by evaluating expression of 12 molecules, consisting of one macrophage (CD68), five immune effector (CD137, CD4, CD7, CD8A, TNFα), and six immune checkpoint (PD-1, PD-L1, PD-L2, TIM3, LAG3, FOXP3) molecules. These were studied in a discovery set of samples from 132 patients with early- and advanced-stage follicular lymphoma who received observation or treatment.

The immune infiltration profile was then investigated in validation cohorts consisting of 138 patients with advanced follicular lymphoma who received rituximab plus cyclophosphamide, vincristine, and prednisone, and 45 who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Immune Infiltration and Risk of Progression

Overall, immune molecules showed distinct clustering by high or low expression irrespective of whether they were immune effector, immune checkpoint, or macrophage molecules.  Four of the markers—PD-L2, TNFα, CD4, and CD68—were significantly associated with clinical outcomes, with low expression of each being associated with poorer outcomes. In analysis adjusting for multiple genes, PD-L2 and TNFα remained significantly associated with outcome, with PD-L2 exhibiting higher specificity and sensitivity.

Low PD-L2 expression in tumors was significantly associated with increased risk of progression of disease within 24 months in the discovery cohort (odds ratio [OR] = 4.32, c-statistic = 0.81, P = .001) and in the validation cohorts among patients treated with rituximab plus cyclophosphamide, vincristine, and prednisone (OR = 2.95, c-statistic = 0.75, P = .011) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (OR = 7.09, c-statistic = 0.88, P = .011).

As stated by the investigators, mutations were equally proportioned across tissues, indicating that degree of immune infiltration represents aspects of follicular lymphoma biology distinct from mutational profile.

The investigators concluded: “Assessment of immune infiltration by PD-L2 expression is a promising tool with which to help identify patients [with follicular lymphoma] who are at risk for progression of disease within 24 months.”

Maher K. Gandhi, MD, PhD, of the Translational Research Institute, Brisbane, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Australian National Health and Medical Research Council, Leukaemia Foundation, Pathology Queensland Study, Education and Research Committee, Celgene, and others. For full disclosures of the study authors, visit jco.ascopubs.org.