# Dynamic immune changes after bone marrow sparing VMAT in women with locally advanced cervical cancer treated with chemoradiotherapy

## TL;DR

Chemoradiotherapy for cervical cancer causes long-term immune suppression, even with bone marrow sparing techniques, highlighting the need for improved treatment strategies.

## Contribution

The study reveals persistent immunosuppression after bone marrow sparing VMAT in cervical cancer patients, despite reduced bone marrow dose.

## Key findings

- Chemoradiotherapy caused immunosuppression lasting 12 months post-treatment.
- BMS VMAT did not prevent grade ≥2 lymphopenia in all patients.
- T-cell response declined despite stable antigen presentation and better proliferation.

## Abstract

•Chemoradiotherapy caused immunosuppression enduring 12 months post-treatment.•Despite bone marrow sparing (BMS) VMAT, all patients developed grade ≥2 lymphopenia.•T-cell response declined despite better proliferation and stable antigen presentation.•Cell lineages shifted from lymphoid to myeloid, mainly from CD4+ T helper and B-cell loss.•Optimizing BMS and exploring other techniques to reduce immunosuppression is needed.

Chemoradiotherapy caused immunosuppression enduring 12 months post-treatment.

Despite bone marrow sparing (BMS) VMAT, all patients developed grade ≥2 lymphopenia.

T-cell response declined despite better proliferation and stable antigen presentation.

Cell lineages shifted from lymphoid to myeloid, mainly from CD4+ T helper and B-cell loss.

Optimizing BMS and exploring other techniques to reduce immunosuppression is needed.

Chemoradiotherapy is immunosuppressive in women with locally advanced cervical cancer (LACC). Both advanced external-beam radiation therapy (EBRT) and bone marrow sparing (BMS) radiotherapy techniques might lower bone marrow dose and therefore reduce the impact on the immune system. In this study, immune composition and function changes in the blood of women with LACC were evaluated for BMS volumetric-modulated arc therapy (VMAT) and exploratively compared with a historical cohort of women with LACC who underwent non-BMS radiotherapy (RT) with older EBRT techniques.

Women were treated with chemoradiotherapy followed by brachytherapy according to EMBRACE-II protocol (BMS VMAT) or with 46–52.5 Gy in 23–30 fractions (non-BMS RT). Blood samples for immunomonitoring were collected at set timepoints. Statistical analyses were performed using linear mixed-effects models.

Eighteen and eleven women received BMS VMAT and non-BMS RT, respectively. Although BMS VMAT reduced mean pelvic bone dose by 8.1 Gy, it did not prevent treatment-induced leukopenia and lymphopenia. Chemoradiotherapy mainly reduced CD4+ T helper cells and B cells, leaving CD8+ T-cell and natural killer-cell frequencies untouched. T-cell reactivity to common pathogens was decreased, despite sustained T-cell proliferative capacity, and coincided with increased numbers of regulatory T cells. The potential to activate immune cells remained intact, with small increases in dendritic cells, decreases in myeloid-derived suppressor cells, and preserved capacity of myeloid cells to present antigen and activate T cells.

Our study provided insight in the dynamic immune changes following chemoradiotherapy in LACC. As immunosuppression occurred with BMS VMAT, optimizing BMS and exploring other techniques is warranted.