# Prognostic Role of Adaptive Immune Microenvironment in Patients with High-Risk Myelodysplastic Syndromes Treated with 5-Azacytidine

## TL;DR

This study shows that immune cell levels in bone marrow biopsies of high-risk MDS patients can predict survival and treatment response to 5-azacytidine.

## Contribution

The study introduces immune cell density as a novel prognostic factor in high-risk myelodysplastic syndromes.

## Key findings

- Higher T and T helper cell densities correlate with better survival and treatment response in HR-MDS patients.
- Increased T regulatory and B cells are associated with worse overall survival in HR-MDS patients.
- A modified IPSS-R incorporating immune parameters improves survival prediction.

## Abstract

Even though immunohistochemistry is routinely used in pathology, there are limited data regarding immune profiling of trephine biopsies from patients with high-risk myelodysplastic syndromes (HR-MDS). We used digital pathology to evaluate the cell densities of adaptive immune cells in trephine biopsies from sixty-four (64) HR-MDS patients with no prior treatment and aimed to correlate these findings with response and overall survival after 5-azacitidine treatment. Increased T regulatory and B cells had adverse effects on overall survival while increased T and T helper cells were beneficial for survival. Similar results were obtained for the response to 5-azacitidine treatment. Our findings support the inclusion of immune cell densities in a modified prognostic score based on the Revised International Prognostic Scoring System (IPSS-R).

Background/Objectives: There are limited data regarding immunohistochemical profiling of immune cells in bone marrow trephine biopsies of patients with high-risk myelodysplastic syndromes (HR-MDS). Methods: We sought to objectively quantify, with the use of digital pathology, the density (cells/mm2) of the prominent adaptive immunity cell populations in sixty-four (64) bone marrow trephine biopsies of HR-MDS patients receiving 5-Azacytidine. We focused on CD3(+) T cells, CD8(+) cytotoxic T cells (Tc), helper T cells (Th), Foxp3(+) regulatory T cells (Tregs), CD20(+) B-cells and CD138(+) plasma cells and evaluated the presence and the number of lymphoid aggregates. A control group of twenty “non-MDS” patients was included in the study. Results: We identified a significant decrease in adaptive immune cell densities in the HR-MDS patients compared to the non-MDS controls. Increased T and Th cell densities correlated with the response to 5-Azacytidine (5-AZA) treatment. Higher T, Tc, Th and plasma cells densities and low B, Tregs and Tregs/T cells ratios correlated with increased overall survival. Reduced Tregs, Tregs/T cells, Tregs/Tc and plasma cells showed improved leukemia-free survival. A modified IPSS-R (IPSS-R-I), combining the initial IPSS-R with the immune populations’ parameters, improved overall survival and showed a double-fold increase in Cox calculated hazard ratios. Conclusions: Immunohistochemical bone marrow immune profiling represents a powerful and easily useable tool for investigating the possible role of bone marrow immune microenvironment in the pathogenesis and progression of MDS, but also its association with the response to 5-AZA treatment and clinical outcomes.