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

Tsz Tung Kwong; Chi Hang Wong; Jing Ying Zhou; Alfred Sze Lok Cheng; Joseph Jao Yiu Sung; Anthony Wing Hung Chan; Stephen Lam Chan

doi:10.1016/j.jhepr.2020.100224

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

JHEP Rep. 2020 Dec 20;3(2):100224. doi: 10.1016/j.jhepr.2020.100224. eCollection 2021 Apr.

Authors

Tsz Tung Kwong¹, Chi Hang Wong¹, Jing Ying Zhou^{2

3}, Alfred Sze Lok Cheng², Joseph Jao Yiu Sung^{4

5}, Anthony Wing Hung Chan³, Stephen Lam Chan⁶

Affiliations

¹ Department of Clinical Oncology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
² School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong.
³ Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong.
⁴ Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
⁵ Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong.

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.

Keywords: 5-FU, fluorouracil; Chemotherapy; HCC, hepatocellular carcinoma; Hepatocellular carcinoma; ICB, immune checkpoint blockade; ICD, immunogenic cell death; Immune checkpoint blockade; Immunotherapy; M-MDSC, mononuclear MDSC; MDSC(s), myeloid-derived suppressor cell(s); Myeloid-derived suppressor cell; NK, natural killer; PD-L1, programmed cell death ligand 1; PMN-MDSC, polymorphonuclear MDSC; TACE; TACE, transarterial chemoembolization; TME, tumor microenvironment; Tumor microenvironment.