Decreased expression of T-cell-associated immune markers predicts poor prognosis in patients with follicular lymphoma

Cancer Sci. 2022 Feb;113(2):660-673. doi: 10.1111/cas.15224. Epub 2021 Dec 5.


We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to 2 cycles of the R-CHOP chemotherapy regimen. The aim of this study was to identify molecular biomarkers that can predict prognosis in RB-treated patients in the context of the prospective cohort. We first analyzed the mutational status of 410 genes in diagnostic tumor specimens by target capture and Sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however none was predictive for progression-free survival (PFS) in the RB-treated patients (n = 34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or the immune response showed that expression levels of CD8+ T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within the 24-mo (POD24) group (n = 8) than in the no POD24 group (n = 31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS using principal component analysis, which dichotomized the RB-treated patients into immune IIShigh (n = 19) and IISlow (n = 20) groups. The 3-y PFS rate was significantly lower in the IISlow group than in the IIShigh group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], P = .0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r = 0.460, P = .00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000 013 795, jRCT:051 180 181).

Keywords: POD24; bendamustine; follicular lymphoma; lymphopenia; tumor microenvironment.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bendamustine Hydrochloride / therapeutic use
  • Biomarkers, Tumor / genetics
  • Female
  • Gene Expression Profiling
  • Humans
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Lymphoma, Follicular / blood
  • Lymphoma, Follicular / drug therapy
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / immunology*
  • Male
  • Middle Aged
  • Mutation
  • Prognosis
  • Progression-Free Survival
  • Rituximab / therapeutic use
  • T-Lymphocytes / metabolism*
  • Treatment Failure
  • Tumor Microenvironment / immunology


  • Biomarkers, Tumor
  • Rituximab
  • Bendamustine Hydrochloride