Abstract 2682: Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients
Authors: Bertuzzi Clara , Tumedei Maria Maddalena , Ravaioli Sara , Agostinelli Claudio , Puccetti Maurizio , Bravaccini Sara , Righi Simona , Casadei Beatrice , Pession Andrea , Martinelli Giovanni , Simonetti Giorgia , Sabattini Elena , De Matteis Serena 
Published: September 2020

Abstract
Follicular lymphoma (FL) still remains an incurable disease, with most of the patients undergoing subsequent phases of remission and relapse.
In the era of immunotherapy, understanding the immunobiology of FL patients who experience progression of disease within 24 months (POD24) and show chemotherapy resistance remains a priority and an unmet clinical need.
Tumor-associated macrophages (TAM) are multifaceted cellular components of the tumor microenvironment (TME). In concert with lymphoid-lineage B and T cells at various developmental stages, TAM can mediate enhanced tumor progression, often leading to poor clinical prognosis and impact the clinical response to chemotherapy. Recently, Joshua and colleagues demonstrated that a subset of FL patients with low immune infiltration was enriched in POD24 events.
In our work, we characterized the immune repertoire of lymph node biopsies collected retrospectively from 30 patients with histological diagnosis of FL according WHO criteria. Median follow up was 8 years. The expression levels of TAM (CD68, CD163, MS4a4a) and tumor-infiltrating T-lymphocytes (CD8, PD-1 positive subsets) were assessed by immunohistochemistry and summarized using descriptive statistics.
Our data highlighted that the subset of patients with a high extrafollicular CD163/CD8 ratio was enriched in POD24 events (p = 0.01). In addition, patients who showed an higher number of intrafollicular CD68+ macrophages, showed a longer disease free survival (p= 0.04).
Another difference was related to the number of CD68, CD163, MS4A4A-positive polarized macrophages that resulted higher in bcl-2 negative than bcl-2 positive cases (p&lt; 0.05 for all markers).
In the evaluation of T lymphocytes, most relevant associations were found between the content and distribution of PD1+ cells and the treatment response: the higher the number of intrafollicular PD1+ lymphocytes the lower chemotherapy response rates (p= 0.04). No association was found between the number of positive elements in extrafollicular areas, where instead the PD1/CD8 ratio seems to be related with therapy response: the higher the ratio the lower response rate (p= 0.01). This finding could be explained assuming that there may be different types of cellular interactions inside and outside the neoplastic follicles.
No other statistically significant difference in terms of expression of these markers was observed in relation to clinical pathological features such as staging, grade and FLIPI score.
In conclusion, extrafollicular high CD163/CD8 ratio is associated with POD24 in FL patients, this finding underlines the pathological significance of CD163-expresing macrophages in TME, suggesting this biomarker as a potential therapeutic target in this disease.
Citation Format: Clara Bertuzzi, Maria Maddalena Tumedei, Sara Ravaioli, Claudio Agostinelli, Maurizio Puccetti, Sara Bravaccini, Simona Righi, Beatrice Casadei, Andrea Pession, Giovanni Martinelli, Giorgia Simonetti, Elena Sabattini, Serena De Matteis. Extrafollicular high CD163/CD8 ratio is associated with progression of disease within 24 months in follicular lymphoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2682.