Prognostic Value of Tumor-Infiltrating TIA-1+ Cytotoxic T Cells (TIA1-CTCs) and FOXP3+ Regulatory T Cells (Tregs) in Post-Transplant Lymphoproliferative Disorder (PTLD) Following Solid Organ Transplant (SOT).
Authors: Tsao Raymond E. , Richendollar Bill , Jin Tony , Hsi Eric , Pohlman Brad 
Published: October 2019

Abstract
Background: PTLD is a rare, often fatal, complication of SOT. Several studies have identified clinical prognostic factors in PTLD. However, no published studies to our knowledge have yet correlated outcome with the number (#) or type of tumor infiltrating T-cells, which in other types of lymphoma may have prognostic value. We hypothesized that tumor infiltrating T-cells, including TIA1-CTCs and Tregs, would predict survival in SOT PTLD.
Methods: We searched the Cleveland Clinic pathology archives for SOT patients (pts), who were diagnosed with PTLD between 1987 and 2007; reviewed the medical records and extracted clinical information and outcomes; performed immunohistochemical (IHC) studies for CD3, TIA-1, and FOXP3; and analyzed the data by Cox proportional univariate and multivariate analyses.
Results: We identified 62 SOT pts (heart, 22; lung, 17; kidney 15; liver, 7; pancreas, 1), who were diagnosed with PTLD at median age of 51 years (range 7–73). The median time from SOT to PTLD was 1.8 years (range 0.2–20.9). 1st therapeutic intervention (1st TI) (usually >1) included “complete” resection (4), decreased immunosuppression (51), acyclovir or gancyclovir (32), rituximab (R) (18), “CHOP” chemotherapy (11), radiation therapy (7), and interferon (4). Response to 1st TI was CR (34) or PR (10). The median follow-up among surviving pts is 3.6 years (range 0.1–11.7). 35 (including 4 CHOP and 9 R) pts have died; only 2 CHOP but all 9 R pts died from PTLD. IHC studies in 42 evaluable cases showed the following median # (and range) of cells /10 hpf: CD3 525 (8–2451), TIA1-CTCs 304 (6–1238) and FOXP3 13 (1–338). On univariate analysis, younger age, prior rejection episodes <2, PS <2, LDH normal, extranodal sites (ENS) <2, IPI <4, 1st TI >1, 1st TI with CHOP, # of CD3 cells >550/10 hpf, and # of TIA1-CTCs >300/10 hpf were associated with an improved overall survival (OS), PTLD-specific survival (PSS), and/or progression-free survival (PFS). On multivariate analyses, only PS <2, ENS <2, and 1st TI with CHOP remained independent predictors of outcome. Among the subset of 47 pts with monomorphic B-cell (MMBC) PTLD, these same clinical factors were also independently statistically significant.
Conclusions: High #s of infiltrating T cells and TIA1-CTCs are associated with a favorable outcome and may reflect a relatively intact local anti-tumor response. Tregs, which may potentially antagonize such a response, are uniformly low and do not correlate with outcome in PTLD. In this analysis, a significant minority of SOT pts treated initially with single agent R still died from PTLD while pts treated initially with CHOP (with or without R) appeared to have a better outcome, arguing for its early use - at least in a subset of pts. Future studies should attempt to identify biological factors that predict which MMBC PTLD pts might benefit from the addition of CHOP to standard R as part of 1st TI.