Peripheral myeloid-derived suppressor and T regulatory PD-1 positive cells predict response to neoadjuvant short-course radiotherapy in rectal cancer patients.

Maria Napolitano,Eleonora Cardone,Anna Maria Trotta,Roberto Pacelli,Ugo Pace,Stefania Scala,Biagio Pecori,Carmela Cacciapuoti,Dario Scala,Crescenzo D’Alterio,Daniela Rega,Fabiana Tatangelo,Paolo Delrio,Giosuè Scognamiglio

doi:10.18632/oncotarget.3014

Abstract

Short-course preoperative radiotherapy (SC-RT) followed by total mesorectal excision (TME) is one therapeutic option for locally advanced rectal cancer (LARC) patients. Since radio-induced DNA damage may affect tumor immunogenicity, Myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) were evaluated in 13 patients undergoing SC-RT and TME for LARC. Peripheral Granulocytic-MDSCs (G-MDSC) [LIN-/HLA-DR-/CD11b+/CD14-/CD15+/CD33+], Monocytic (M-MDSC) [CD14+/HLA-DR-/lowCD11b+/CD33+] and Tregs [CD4+/CD25hi+/FOXP3+- CTLA-4/PD1] basal value was significantly higher in LARC patients compared to healthy donors (HD). Peripheral MDSC and Tregs were evaluated at time 0 (T0), after 2 and 5 weeks (T2-T5) from radiotherapy; before surgery (T8) and 6-12 months after surgery (T9, T10). G-MDSC decreased at T5 and further at T8 while M-MDSC cells decreased at T5; Tregs reached the lowest value at T5. LARC poor responder patients displayed a major decrease in M-MDSC after SC-RT and an increase of Treg-PD-1. In this pilot study MDSCs and Tregs decrease during the SC-RT treatment could represent a biomarker of response in LARC patients. Further studies are needed to confirm that the deepest M-MDSC reduction and increase in Treg-PD1 cells within 5-8 weeks from the beginning of treatment could discriminate LARC patients poor responding to SC-RT.

Highlights

Microenvironment (ME) surrounding cancer cells has been shown to be profoundly involved in the biological behaviour of tumours
As previously reported [21], a significantly higher number of circulating G-Myeloidderived suppressor cells (MDSCs) and M-MDSC was detected in locally advanced rectal cancer (LARC) patients at time 0 compared to healthy donors (Figure 3A–3B); T regulatory cells (Tregs) (CD4+/CD25hi+/ FoxP3+/CTLA4+ and CD4+/CD25hi+/FoxP3+/PD1+) were higher in LARC patients compared to healthy donors (Figure 3C–3D)
G-MDSC decreased at T5 and further at T8 while M-MDSC cells decreased at T5 being stable up to T8 (Figure 4A–4B); Tregs reached the lowest value at five weeks after the beginning of Short-course preoperative radiotherapy (SC-radiation therapy (RT)) (Figure 4C–4D)

Summary

Introduction

Microenvironment (ME) surrounding cancer cells has been shown to be profoundly involved in the biological behaviour of tumours. Through an active humoral and physical cross talk ME can determine invasion, ability to metastasize, immunogenicity of cancer and response to anticancer therapies including radiation therapy (RT). The effects of radiotherapy reported on tumor cells are conflicting, and the general belief on immunity is that different microenvironments and diverse delivery modalities may induce activation or inhibition of www.impactjournals.com/oncotarget immune response and the size of fraction is one of the variables involved in such a dualism [1,2,3]. The management of the middle and low rectum LARC includes neoadjuvant radiotherapy (NRT) [6] that has been shown to be less toxic and more effective in improving local control than postoperative RT [7]. More recently delayed surgery after SC-RT has been proposed [11, 12] for high risk LARC patients in association with chemotherapy [12]

Methods

Results

Conclusion