Neoadjuvant Radiochemotherapy Significantly Alters the Phenotype of Plasmacytoid Dendritic Cells and 6-Sulfo LacNAc+ Monocytes in Rectal Cancer.

Felix Wagner,Marc Schmitz,Christoph Reißfelder,Rebekka Wehner,Martin Bornhäuser,Ulrich Sommer,Jürgen Weitz,Ioana Plesca,Knut Schäkel,Maximilian Kießler,Maia Arsova,Gustavo Baretton,Ulrike Hölig,Mechthild Krause,Antje Tunger,Armin Jarosch,Andreas Bogner,Katharina Flecke,Friederike Wilczkowski,Gunnar Folprecht,Daniela E Aust ,Michael Bachmann ,Esther G.c Troost

doi:10.3389/fimmu.2019.00602

Abstract

Neoadjuvant radiochemotherapy (nRCT) can significantly influence the tumor immune architecture that plays a pivotal role in regulating tumor growth. Whereas, various studies have investigated the effect of nRCT on tumor-infiltrating T cells, little is known about its impact on the frequency and activation status of human dendritic cells (DCs). Plasmacytoid DCs (pDCs) essentially contribute to the regulation of innate and adaptive immunity and may profoundly influence tumor progression. Recent studies have revealed that higher pDC numbers are associated with poor prognosis in cancer patients. 6-sulfo LacNAc-expressing monocytes (slanMo) represent a particular proinflammatory subset of human non-classical blood monocytes that can differentiate into DCs. Recently, we have reported that activated slanMo produce various proinflammatory cytokines and efficiently stimulate natural killer cells and T lymphocytes. slanMo were also shown to accumulate in clear cell renal cell carcinoma (ccRCC) and in metastatic lymph nodes from cancer patients. Here, we investigated the influence of nRCT on the frequency of rectal cancer-infiltrating pDCs and slanMo. When evaluating rectal cancer tissues obtained from patients after nRCT, a significantly higher density of pDCs in comparison to pre-nRCT tissue samples was found. In contrast, the density of slanMo was not significantly altered by nRCT. Further studies revealed that nRCT significantly enhances the proportion of rectal cancer-infiltrating CD8+ T cells expressing the cytotoxic effector molecule granzyme B. When exploring the impact of nRCT on the phenotype of rectal cancer-infiltrating pDCs and slanMo, we observed that nRCT markedly enhances the percentage of inducible nitric oxide synthase (iNOS)- or tumor necrosis factor (TNF) alpha-producing slanMo. Furthermore, nRCT significantly increased the percentage of mature CD83+ pDCs in rectal cancer tissues. Moreover, the proportion of pDCs locally expressing interferon-alpha, which plays a major role in antitumor immunity, was significantly higher in post-nRCT tissues compared to pre-nRCT tumor specimens. These novel findings indicate that nRCT significantly influences the frequency and/or phenotype of pDCs, slanMo, and CD8+ T cells, which may influence the clinical response of rectal cancer patients to nRCT.

Highlights

Colorectal cancer is one of the most common malignancies in the United States with an estimated incidence of 140,250 cases and an estimated number of 50,630 deaths in 2018 [1]
It has been shown that high densities of CD45RO+ T helper (Th) 1 cells and CD8+ T cells are associated with improved survival of colorectal cancer patients [3, 4]
NRCT Significantly Increases the Frequency of pDCs in Rectal Cancer pDCs essentially contribute to the regulation of innate and adaptive immunity and may play an important role in the immune defense against tumors

Summary

INTRODUCTION

Colorectal cancer is one of the most common malignancies in the United States with an estimated incidence of 140,250 cases and an estimated number of 50,630 deaths in 2018 [1]. It has been reported that several chemotherapeutic agents as well as radiotherapy can efficiently stimulate antitumor immune responses by triggering immunogenic cell death in tumor cells [12, 13]. This process is characterized by the translocation of intracellular calreticulin to the surface of tumor cells and the release of high-mobility-group box 1. Inhibition of CD47 function significantly augments the engulfment of tumor cells by DCs, resulting in effective antitumor responses [16] In contrast to these immunostimulatory effects, radiotherapy, and chemotherapeutic agents can induce immunosuppressive effects. Following recent findings, indicating that IFNα essentially contributes to the antitumor effects mediated by RCT, the influence of nRCT on the proportion of rectal cancerinfiltrating pDCs locally expressing this cytokine was evaluated

MATERIALS AND METHODS

RESULTS

ETHICS STATEMENT