Rituximab treatment circumvents the prognostic impact of tumor-infiltrating T-cells in follicular lymphoma patients

• Published in: Human pathology Vol. 64; pp. 128 - 136
• Main Authors: Xerri, Luc, Huet, Sarah, Venstrom, Jeffrey M., Szafer-Glusman, Edith, Fabiani, Bettina, Canioni, Danielle, Chassagne-Clément, Catherine, Dartigues-Cuilléres, Peggy, Charlotte, Fréderic, Laurent, Camille, Gelas-Dore, Benedicte, Bolen, Christopher R., Punnoose, Elizabeth, Bouabdallah, Reda, Brice, Pauline, Morschhauser, Franck, Cartron, Guillaume, Olive, Daniel, Salles, Gilles
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2017; Elsevier Limited
• Subjects: Antineoplastic Agents - therapeutic use; Automation; Biomarkers; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biopsy; Cancer therapies; CD3 Complex - analysis; CD3 Complex - genetics; Cloning; Cytotoxicity; Disease-Free Survival; Follicular lymphoma; Gene expression; Humans; Image Interpretation, Computer-Assisted; Immunohistochemistry; Immunotherapy; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphoma; Lymphoma, Follicular - drug therapy; Lymphoma, Follicular - genetics; Lymphoma, Follicular - immunology; Lymphoma, Follicular - pathology; Microenvironment; Monoclonal antibodies; Pathology; Patients; Predictive Value of Tests; Prognosis; Rituximab - therapeutic use; RNA, Messenger - genetics; RNAseq; Sequence Analysis, RNA; Studies; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Targeted cancer therapy; Time Factors; Treatment Outcome; Tumor Microenvironment; Immunohistochemistry; Follicular lymphoma; Prognosis; Microenvironment; RNAseq
• ISSN: 0046-8177; 1532-8392; 1532-8392
• DOI: 10.1016/j.humpath.2017.03.023

Previous immunohistochemical (IHC) studies showed controversial data about the prognostic value of tumor-infiltrating lymphocytes (TILs) in follicular lymphoma (FL). To clarify this issue, a large series of FL samples from rituximab-treated patients enrolled in the randomized PRIMA trial was examined. IHC was quantified using automated image analysis in 417, 287, 418, 406, 379, and 369 patients for CD3, CD4, CD8, PD1, ICOS, and FOXP3, respectively. RNAseq analysis was used to quantify TIL-related mRNA transcripts from 148 patients. When each IHC marker was used as a continuous variable in the whole cohort, high CD3 counts were associated with better progression-free survival (PFS) (P = .025). When an optimal IHC cut point was applied to the whole patient population, high CD3 counts and high PD1 counts were associated with better PFS (P = .011 and P = .044, respectively), whereas none of the other TIL markers had any significant correlation with outcome. When a stringent analysis was performed by dividing the whole cohort into a training set and a validation set, none of the TIL markers showed a prognostic significance in both groups. RNAseq analysis showed a significant correlation between high levels of CD3 and CD8 transcripts and better PFS (P = .001 and P = .037, respectively). No prognostic correlation was found as to the level of other immune gene transcripts. These results suggest that the IHC prognostic value of TILs is circumvented by rituximab treatment, although there is a trend for high numbers of CD3+ TILs to correlate with better PFS. •In rituximab-treated FL patients, CD3+ cells are a prognostic indicator of better survival.•CD3+ cells are the strongest prognostic indicator compared to other classical TIL subsets.•The lack of robustness of the CD3 predictive value argues against its usefulness in routine practice.