PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival

Abstract

To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1+ T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD-1 is expressed on intratumoral CD4+ T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4+PD-1high T cells predominantly reside in the lymph node follicles, while PD-1low T cells are mainly located in an interfollicular pattern. Intratumoral CD4+PD-1high T cells have a TFH cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4+PD-1low T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4+PD-1high T cells actively supported B-cell growth, while CD4+PD-1low T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4+ or CD8+PD-1low T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4+PD-1high T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL.

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…65 Recently, the same Mayo Clinic group described in the "Treg cells" section reported that PD1 was expressed in intratumoral CD4 + T cells with both bright and dim intensity, representing two different sub-populations of cells. 66 By IHC, CD4 + PD1 high T cells were found predominantly localized to the LN follicles, whereas PD1 low T-cells were mainly in interfollicular areas. Intratumoral CD4 + PD1 high T cells showed a TFH-cell phenotype: CXCR5 expression and secretion of IL-21 (left upper corner of Fig.…”

“…On the contrary, the proportion of CD4 + PD1 high T cells (cutoff value, 25%) was not associated with patient outcome. 66 Furthermore, in the 14th International Conference on Malignant Lymphoma, the French group reported that PD1 + TFH cells did not have any prognostic significance in FL patients enrolled in the PRIMA trial. 67 Another Mayo Clinic group analyzed serial biopsy specimens of 58 FL patients by localization pattern and cell content.…”

The emerging role of immune checkpoint inhibition in malignant lymphoma

“…54 Despite several attempts at translating these findings into immunohistochemical studies and clinical practice, results are still inconclusive. 55,56 Similarily, attempts to distinguish the prognostic impact of PD-1 expression in the FL tumor microenvironement on survival have resulted in controversial findings, possibly due to technical issues and different prior treatment regimens including different rituximab utilization within the tested cohorts. [57][58][59] Ten FL patients were included in a phase I study of nivolumab in a variety of r/r hematologic malignancies; 47 the ORR was 40% and three responses were ongoing after a median follow-up of 91.4 weeks, which encouraged further clinical trials.…”

Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

“…Several studies have focused on localization patterns of TFH cells. While PD-1 expression generally correlated with T-cell content in both interfollicular and follicular zones, it was mainly expressed within 52 55 Others identified distinct functional T-cell populations displaying specific gene expression profiles on the basis of CD25, namely CD25 + follicular regulatory T cells and CD25-T FH . 43 Changes in PD-1, PD-L1 and PD-L2 expression were analyzed with pidilizumab and rituximab treatment in relapsed FL patients.…”

“…Expression of PD-1 and PD-L1 on tumor infiltrating lymphocytes (TILs) and tumor cells in FL. 55 A potential prognostic role has also been attributed to patterns of PD-1 + TILs. The prognostic values of CD4 + and PD-1 + cells were accentuated when they were follicular, and that of CD8 + cells when they were interfollicular.…”