Top

Journal of Experimental & Clinical Cancer Research

Published in:

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

S100A9⁺CD14⁺ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function

Authors: Xiaoxuan Tu, Longxian Chen, Yi Zheng, Chenglin Mu, Zhiwei Zhang, Feiyu Wang, Yiqing Ren, Yingxin Duan, Hangyu Zhang, Zhou Tong, Lulu Liu, Xunqi Sun, Peng Zhao, Lie Wang, Xinhua Feng, Weijia Fang, Xia Liu

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

The paucity of reliable biomarkers for predicting immunotherapy efficacy in patients with advanced hepatocellular carcinoma (HCC) has emerged as a burgeoning concern with the expanding use of immunotherapy. This study endeavors to delve into the potential peripheral biomarkers capable of prognosticating efficacy in HCC patients who are poised to receive anti-PD-1 monotherapy within the phase III clinical trial, KEYNOTE394. Additionally, we sought to elucidate the underlying molecular mechanisms for resistance to immune checkpoint blockade (ICB) and propose innovative combination immunotherapy strategies for future clinical application.

Methods

Patient blood samples were collected for single-cell RNA sequencing to evaluate the immune cell signature before receiving ICB therapy. Subsequently, in vitro assays and in vivo murine model experiments were conducted to validate the mechanism that S100A9⁺CD14⁺ monocytes play a role in ICB resistance.

Results

Our study demonstrates a notable enrichment of S100A9⁺CD14⁺ monocytes in the peripheral blood of patients exhibiting suboptimal responses to anti-PD-1 therapy. Moreover, we identified the Mono_S100A9 signature as a predictive biomarker, indicative of reduced efficacy in immunotherapy and decreased survival benefits across various tumor types. Mechanistically, S100A9 activates PD-L1 transcription by directly binding to the CD274 (PD-L1) gene promoter, thereby suppressing T-cell proliferation and cytotoxicity via the PD-1/PD-L1 axis, consequently diminishing the therapeutic effectiveness of subsequent anti-PD-1 treatments. Furthermore, our in vivo studies revealed that inhibiting S100A9 can synergistically enhance the efficacy of anti-PD-1 drugs in the eradication of hepatocellular carcinoma.

Conclusions

Our study underscores the significance of S100A9⁺CD14⁺ monocytes in predicting inadequate response to ICB treatment and provides insights into the monocyte cell-intrinsic mechanisms of resistance to ICB therapy. We also propose a combined therapeutic approach to enhance ICB efficacy by targeting S100A9.

Available only for authorised users

El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (London, England). 2017;389(10088):2492–502.PubMedCrossRef

Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52.PubMedCrossRef

Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020;21(4):571–80.PubMedCrossRef

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–905.PubMedCrossRef

Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, et al. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label. Phase II Trial Clin Cancer Res. 2021;27(4):1003–11.PubMed

Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151–72.PubMedCrossRef

Shiuan E, Reddy A, Dudzinski SO, Lim AR, Sugiura A, Hongo R, et al. Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma. Cancers. 2021;13(6):1475. https://doi.org/10.3390/cancers13061475.

Yuen KC, Liu LF, Gupta V, Madireddi S, Keerthivasan S, Li C, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat Med. 2020;26(5):693–8.PubMedPubMedCentralCrossRef

Mazzaschi G, Minari R, Zecca A, Cavazzoni A, Ferri V, Mori C, et al. Soluble PD-L1 and Circulating CD8+PD-1+ and NK Cells Enclose a Prognostic and Predictive Immune Effector Score in Immunotherapy Treated NSCLC patients. Lung Cancer. 2020;148:1–11.PubMedCrossRef

10.

Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, et al. Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer. Cancer Discov. 2021;11(9):2168–85.PubMedCrossRef

11.

Puig-Saus C, Sennino B, Peng S, Wang CL, Pan Z, Yuen B, et al. Neoantigen-targeted CD8(+) T cell responses with PD-1 blockade therapy. Nature. 2023;615(7953):697–704.ADSPubMedPubMedCentralCrossRef

12.

Hogan SA, Courtier A, Cheng PF, Jaberg-Bentele NF, Goldinger SM, Manuel M, et al. Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma. Cancer Immunol Res. 2019;7(1):77–85.PubMedCrossRef

13.

Han J, Duan J, Bai H, Wang Y, Wan R, Wang X, et al. TCR Repertoire Diversity of Peripheral PD-1(+)CD8(+) T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer. Cancer Immunol Res. 2020;8(1):146–54.PubMedCrossRef

14.

Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, et al. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind. Phase III Trial J Clin Oncol. 2023;41(7):1434–43.PubMed

15.

Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36(5):411–20.PubMedPubMedCentralCrossRef

16.

Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell. 2019;176(1–2):404.PubMedPubMedCentralCrossRef

17.

Sun Y, Wu L, Zhong Y, Zhou K, Hou Y, Wang Z, et al. Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma. Cell. 2021;184(2):404-21.e16.PubMedCrossRef

18.

Ho DW-H, Tsui Y-M, Chan L-K, Sze KM-F, Zhang X, Cheu JW-S, et al. Single-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma. Nature Communications. 2021;12(1):3684.ADSPubMedPubMedCentralCrossRef

19.

Lánczky A, Győrffy B. Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. J Med Internet Res. 2021;23(7): e27633.PubMedPubMedCentralCrossRef

20.

Sivori S, Pende D, Quatrini L, Pietra G, Della Chiesa M, Vacca P, et al. NK cells and ILCs in tumor immunotherapy. Mol Aspects Med. 2021;80: 100870.PubMedCrossRef

21.

Xie Y, Xie F, Zhang L, Zhou X, Huang J, Wang F, et al. Targeted Anti-Tumor Immunotherapy Using Tumor Infiltrating Cells. Adv Sci (Weinh). 2021;8(22): e2101672.PubMedCrossRef

22.

Cambier S, Gouwy M, Proost P. The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol. 2023;20(3):217–51.PubMedPubMedCentralCrossRef

23.

Schalper KA, Carleton M, Zhou M, Chen T, Feng Y, Huang SP, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26(5):688–92.PubMedPubMedCentralCrossRef

24.

Colicchia M, Schrottmaier WC, Perrella G, Reyat JS, Begum J, Slater A, et al. S100A8/A9 drives the formation of procoagulant platelets through GPIbα. Blood. 2022;140(24):2626–43.PubMedPubMedCentralCrossRef

25.

Wang S, Song R, Wang Z, Jing Z, Wang S, Ma J. S100A8/A9 in Inflammation. Front Immunol. 2018;9:1298.PubMedPubMedCentralCrossRef

26.

Hung HC, Lee JC, Wang YC, Cheng CH, Wu TH, Lee CF, et al. Response Prediction in Immune Checkpoint Inhibitor Immunotherapy for Advanced Hepatocellular Carcinoma. Cancers. 2021;13(7).

27.

Wagner NB, Weide B, Gries M, Reith M, Tarnanidis K, Schuermans V, et al. Tumor microenvironment-derived S100A8/A9 is a novel prognostic biomarker for advanced melanoma patients and during immunotherapy with anti-PD-1 antibodies. J Immunother Cancer. 2019;7(1):343.PubMedPubMedCentralCrossRef

28.

Lozano AX, Chaudhuri AA, Nene A, Bacchiocchi A, Earland N, Vesely MD, et al. T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma. Nat Med. 2022;28(2):353–62.PubMedPubMedCentralCrossRef

29.

Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382–6.ADSPubMedPubMedCentralCrossRef

30.

Song R, Struhl K. S100A8/S100A9 cytokine acts as a transcriptional coactivator during breast cellular transformation. 2021;7(1):eabe5357.

31.

Ugel S, Canè S, De Sanctis F, Bronte V. Monocytes in the Tumor Microenvironment. Annu Rev Pathol. 2021;16:93–122.PubMedCrossRef

32.

Bao X, Wang D, Dai X, Liu C, Zhang H, Jin Y, et al. An immunometabolism subtyping system identifies S100A9(+) macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis. Cell Rep Med. 2023;4(4): 100987.PubMedPubMedCentralCrossRef

33.

Camidge DR, Doebele RC, Kerr KM. Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC. Nat Rev Clin Oncol. 2019;16(6):341–55.PubMedCrossRef

34.

Nishino M, Ramaiya NH, Hatabu H, Hodi FS. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat Rev Clin Oncol. 2017;14(11):655–68.PubMedPubMedCentralCrossRef

35.

Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab. Cell. 2017;171(4):934-49.e16.PubMedPubMedCentralCrossRef

36.

Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2017;168(3):542.PubMedCrossRef

37.

Carbone DP, Reck M, Paz-Ares L, Creelan B, Horn L, Steins M, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376(25):2415–26.PubMedPubMedCentralCrossRef

38.

Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.PubMedPubMedCentralCrossRef

39.

Madore J, Strbenac D, Vilain R, Menzies AM, Yang JY, Thompson JF, et al. PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma. Clin Cancer Res. 2016;22(15):3915–23.PubMedCrossRef

40.

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–22.PubMedCrossRef

41.

Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019;37(7):537–46.PubMedCrossRef

42.

Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23(1):77–90.PubMedCrossRef

43.

Aguiar PN Jr, Santoro IL, Tadokoro H, de Lima LG, Filardi BA, Oliveira P, et al. The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: a network meta-analysis. Immunotherapy. 2016;8(4):479–88.PubMedCrossRef

44.

Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010;327(5966):656–61.ADSPubMedPubMedCentralCrossRef

45.

Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12(4):269–81.PubMedPubMedCentralCrossRef

46.

DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19(6):369–82.PubMedPubMedCentralCrossRef

47.

Gentek R, Molawi K, Sieweke MH. Tissue macrophage identity and self-renewal. Immunol Rev. 2014;262(1):56–73.PubMedCrossRef

48.

Chuah S, Lee J, Song Y, Kim HD, Wasser M, Kaya NA, et al. Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma. J Hepatol. 2022;77(3):683–94.PubMedCrossRef

49.

Patil NS, Nabet BY, Müller S, Koeppen H, Zou W, Giltnane J, et al. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer Cell. 2022;40(3):289-300.e4.PubMedCrossRef

50.

De Biasi S, Gibellini L, Lo Tartaro D, Puccio S, Rabacchi C, Mazza EMC, et al. Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy. Nat Commun. 2021;12(1):1669.ADSPubMedPubMedCentralCrossRef

51.

Rad Pour S, Pico de Coaña Y, Demorentin XM, Melief J, Thimma M, Wolodarski M, et al. Predicting anti-PD-1 responders in malignant melanoma from the frequency of S100A9+ monocytes in the blood. J Immunother Cancer. 2021;9(5).

52.

Guida M, Bartolomeo N, Quaresmini D, Quaglino P, Madonna G, Pigozzo J, et al. Basal and one-month differed neutrophil, lymphocyte and platelet values and their ratios strongly predict the efficacy of checkpoint inhibitors immunotherapy in patients with advanced BRAF wild-type melanoma. J Transl Med. 2022;20(1):159.PubMedPubMedCentralCrossRef

53.

Hwang M, Canzoniero JV, Rosner S, Zhang G, White JR, Belcaid Z, et al. Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy. J Immunother Cancer. 2022;10(6).

54.

Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, et al. Dynamic CD8(+) T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 2023;186(6):1127-43.e18.PubMedCrossRef

55.

Yost KE, Satpathy AT, Wells DK, Qi Y, Wang C, Kageyama R, et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 2019;25(8):1251–9.PubMedPubMedCentralCrossRef

56.

Huang Q, Wu X, Wang Z, Chen X, Wang L, Lu Y, et al. The primordial differentiation of tumor-specific memory CD8(+) T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell. 2022;185(22):4049-66.e25.PubMedCrossRef

57.

Fang W, Zhou T, Shi H, Yao M, Zhang D, Qian H, et al. Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8(+) T cell exclusion. J Exp Clin Cancer Res. 2021;40(1):4.PubMedPubMedCentralCrossRef

58.

Yin Y, Liu B, Cao Y, Yao S, Liu Y, Jin G, et al. Colorectal Cancer-Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating PD-L1 Expression in Tumor-Associated Macrophages. Adv Sci (Weinh). 2022;9(9):2102620.PubMedCrossRef

59.

Diskin B, Adam S, Cassini MF, Sanchez G, Liria M, Aykut B, et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol. 2020;21(4):442–54.PubMedCrossRef

60.

Peng Q, Qiu X, Zhang Z, Zhang S, Zhang Y, Liang Y, et al. PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade. Nat Commun. 2020;11(1):4835.ADSPubMedPubMedCentralCrossRef

61.

Que H, Fu Q, Lan T, Tian X, Wei X. Tumor-associated neutrophils and neutrophil-targeted cancer therapies. Biochim Biophys Acta. 2022;1877(5): 188762.

62.

Yang R, Zhang W, Shang X, Chen H, Mu X, Zhang Y, et al. Neutrophil-related genes predict prognosis and response to immune checkpoint inhibitors in bladder cancer. Front Pharmacol. 2022;13:1013672.PubMedPubMedCentralCrossRef

63.

Parikh K, Kumar A, Ahmed J, Anwar A, Puccio C, Chun H, et al. Peripheral monocytes and neutrophils predict response to immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer. Cancer Immunol Immunother. 2018;67(9):1365–70.PubMedCrossRef

64.

Singhal S, Bhojnagarwala PS, O’Brien S, Moon EK, Garfall AL, Rao AS, et al. Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer. Cancer Cell. 2016;30(1):120–35.PubMedPubMedCentralCrossRef

65.

Li J, Shu X, Xu J, Su SM, Chan UI, Mo L, et al. S100A9-CXCL12 activation in BRCA1-mutant breast cancer promotes an immunosuppressive microenvironment associated with resistance to immunotherapy. Nat Commun. 2022;13(1):1481.ADSPubMedPubMedCentralCrossRef

Title: S100A9+CD14+ monocytes contribute to anti-PD-1 immunotherapy resistance in advanced hepatocellular carcinoma by attenuating T cell-mediated antitumor function
Authors: Xiaoxuan Tu
Longxian Chen
Yi Zheng
Chenglin Mu
Zhiwei Zhang
Feiyu Wang
Yiqing Ren
Yingxin Duan
Hangyu Zhang
Zhou Tong
Lulu Liu
Xunqi Sun
Peng Zhao
Lie Wang
Xinhua Feng
Weijia Fang
Xia Liu
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Biomarkers
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-02985-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

IL6-STAT3-C/EBPβ-IL6 positive feedback loop in tumor-associated macrophages promotes the EMT and metastasis of lung adenocarcinoma

N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1

PARD3 drives tumorigenesis through activating Sonic Hedgehog signalling in tumour-initiating cells in liver cancer

Anaplastic thyroid cancer spheroids as preclinical models to test therapeutics

Correction: c-Myc-activated long non-coding RNA LINC01050 promotes gastric cancer growth and metastasis by sponging miR-7161-3p to regulate SPZ1 expression

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes

Keynote webinar | Spotlight on antibody–drug conjugates in cancer