Chemotherapy-induced recruitment of myeloid-derived suppressor cells abrogates efficacy of immune checkpoint blockade

Abstract

Background & aims Immune checkpoint blockade (ICB) has been approved for treatment of hepatocellular carcinoma (HCC). However, many patients with advanced HCC are non-responders to ICB monotherapy. Cytotoxic chemotherapy has been proposed to modulate the tumor microenvironment (TME) and sensitize tumors to ICB. Thus, we aimed to study the combination of cytotoxic chemotherapy and ICB in an orthotopic HCC model. Methods Preclinical orthotopic HCC mouse models were used to elucidate the efficacy of 5-fluorouracil (5-FU) and ICB. The mice were intrahepatically injected with RIL-175 or Hepa1-6 cells, followed by treatment with 5-FU and anti-programmed cell death ligand 1 (PD-L1) antibody. Myeloid-derived suppressor cells (MDSCs) were depleted to validate their role in attenuating sensitivity to immunotherapy. Flow cytometry-based immune profiling and immunofluorescence staining were performed in mice and patient samples, respectively. Results 5-FU could induce intratumoral MDSC accumulation to counteract the infiltration of T lymphocytes and natural killer cells, thus abrogating the anti-tumor efficacy of PD-L1 blockade. In clinical samples, MDSCs accumulated and CD8 + T cell numbers decreased following transarterial chemoembolization. Conclusion 5-FU can trigger the accumulation of immunosuppressive MDSCs, impairing the response to PD-L1 blockade in HCC. Our data suggest that the combination of specific chemotherapy and ICB may impair anti-tumor immune responses, warranting further study in preclinical models and consideration in clinical settings. Lay summary Our findings suggest that some chemotherapies may impair the anti-tumor efficacy of immunotherapy. Further studies are required to uncover the specific effects of different chemotherapies on the immunological profile of tumors. This data will be critical for the rational design of combination immunotherapy strategies for patients with hepatocellular carcinoma.

Early changes in peripheral blood cytokine levels after the treatment of metastatic hepatic carcinoma with CalliSpheres microspheres drug-eluting beads transcatheter arterial chemoembolization

“…Therefore, although the recent changes in the immune-inflammatory network after CSM-TACE were complex, there was still overall consistency of changes, which further suggested that the simultaneous presence of acute inflammatory response and immune antitumor response may be a typical short-term postoperative CSM-TACE immunological phenomenon, the changes in IL-6 and Il-17A levels were more significant, but the changes in IFN-r and CD4 + /CD8 + T levels seem to be more specific. In addition, the chemotherapy drugs and dosages used in TACE may also cause different immune responses (22,23). The chemotherapeutic drugs of CSM-TACE dominated by drug-loaded microspheres are slowly released in the liver tumor, which may be the main reason for its great difference from other conventional TACE.…”

Chemotherapy-induced complement signaling modulates immunosuppression and metastatic relapse in breast cancer

“…Adjuvant doxorubicin enhanced the recruitment of MDSCs to the lung metastatic niche, and led to boosting of the immunosuppressive phenotype of these cells, thus limiting anti-tumor immunity by enhancing T cell dysfunction. Chemotherapy-induced infiltration of MDSCs was previously observed in mouse models of primary tumors 66 , 67 . Our findings in a spontaneous metastatic setting suggest that systemic effects of adjuvant therapy may nurture an immunosuppressive metastatic niche.…”

Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma

“…Recently, it has been demonstrated that chemotherapy can efficiently stimulate the antitumor immune response by triggering immunogenic cell death [ 39 , 40 , 41 ]. In contrast, chemotherapy can also induce immunosuppressive effects, including the increase in tumor-promoting MDSCs [ 41 , 42 , 43 ]. In addition, it has been reported that neoadjuvant chemotherapy results in an increased frequency of PDAC-infiltrating CD4 + and CD8 + T cells, while the density of Tregs and MDSCs decreases [ 44 , 45 , 46 , 47 ].…”