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05.04.2023 | Research

Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models

verfasst von: Hiroyuki Takahashi, Nao Miyoshi, Hisashi Murakami, Yuta Okamura, Naohisa Ogo, Akimitsu Takagi, Daisuke Muraoka, Akira Asai

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 7/2023

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Abstract

The signal transducer and activator of transcription 3 (STAT3) signaling pathway is a key mediator of cancer cell proliferation, survival, and invasion. We discovered YHO-1701 as a small molecule inhibitor of STAT3 dimerization and demonstrated its potent anti-tumor activity using xenograft mouse models as monotherapy and combination therapy with molecular targeted drugs. STAT3 is also associated with cancer immune tolerance; therefore, we used the female CT26 syngeneic mouse model to examine the effect of combining YHO-1701 administration with PD-1/PD-L1 blockade. Pretreatment of the mice with YHO-1701 before starting anti-PD-1 antibody administration resulted in a significant therapeutic effect. In addition, the effect of monotherapy and combination treatment with YHO-1701 was significantly abolished by depleting natural killer (NK) cell activity. YHO-1701 was also found to restore the activity of mouse NK cells under inhibitory conditions in vitro. Furthermore, this combination therapy significantly inhibited tumor growth in an immunotherapy-resistant model of murine CMS5a fibrosarcoma. These results suggest that the combination of YHO-1701 with PD-1/PD-L1 blockade might be a new candidate for cancer immunotherapy involving the enhancement of NK cell activity in the tumor microenvironment.

Nishisaka F, Taniguchi K, Tsugane M, Hirata G, Takagi A, Asakawa N et al (2020) Antitumor activity of a novel oral signal transducer and activator of transcription 3 inhibitor YHO-1701. Cancer Sci 111:1774–1784. https://doi.org/10.1111/cas.14369CrossRefPubMedPubMedCentral

Taniguchi K, Konishi H, Yoshinaga A, Tsugane M, Takahashi H, Nishisaka F et al (2021) Efficacy of combination treatment using YHO-1701, an orally active STAT3 inhibitor, with molecular-targeted agents on cancer cell lines. Sci Rep 11:6685. https://doi.org/10.1038/s41598-021-86021-8CrossRefPubMedPubMedCentral

Yanagimura N, Takeuchi S, Fukuda K, Arai S, Tanimoto A, Nishiyama A et al (2022) STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis. NPJ Precis Oncol 6:11. https://doi.org/10.1038/s41698-022-00254-yCrossRefPubMedPubMedCentral

Zou S, Tong Q, Liu B, Huang W, Tian Y, Fu X (2020) Targeting STAT3 in cancer immunotherapy. Mol Cancer 19:145. https://doi.org/10.1186/s12943-020-01258-7CrossRefPubMedPubMedCentral

Rébé C, Ghiringhelli F (2019) STAT3, a master regulator of anti-tumor immune response. Cancers (Basel) 11:1280. https://doi.org/10.3390/cancers11091280CrossRefPubMed

Johnson DE, O’Keefe RA, Grandis JR (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15:234–248. https://doi.org/10.1038/nrclinonc.2018.8CrossRefPubMedPubMedCentral

Kwon YJ, Seo EB, Jeong AJ, Lee SH, Noh KH, Lee S et al (2022) The acidic tumor microenvironment enhances PD-L1 expression via activation of STAT3 in MDA-MB-231 breast cancer cells. BMC Cancer 22:852. https://doi.org/10.1186/s12885-022-09956-9CrossRefPubMedPubMedCentral

Liu F, Huang J, He F, Ma X, Fan F, Meng M et al (2020) CD96, a new immune checkpoint, correlates with immune profile and clinical outcome of glioma. Sci Rep 10:10768. https://doi.org/10.1038/s41598-020-66806-zCrossRefPubMedPubMedCentral

De Martino M, Tkach M, Bruni S, Rocha D, Mercogliano MF, Cenciarini ME et al (2020) Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable for cancer immunotherapy. Oncoimmunology 9:1715767. https://doi.org/10.1080/2162402x.2020.1715767CrossRefPubMedPubMedCentral

10.

Huang L, Xu Y, Fang J, Liu W, Chen J, Liu Z et al (2021) Targeting STAT3 abrogates Tim-3 upregulation of adaptive resistance to PD-1 blockade on regulatory T cells of melanoma. Front Immunol 12:654749. https://doi.org/10.3389/fimmu.2021.654749CrossRefPubMedPubMedCentral

11.

Kim TW, Kim Y, Keum H, Jung W, Kang M, Jon S (2022) Combination of a STAT3 inhibitor with anti-PD-1 immunotherapy is an effective treatment regimen for a vemurafenib-resistant melanoma. Mol Ther Oncolytics 26:1–14. https://doi.org/10.1016/j.omto.2022.06.001CrossRefPubMedPubMedCentral

12.

Ribrag V, Lee ST, Rizzieri D, Dyer MJS, Fayad L, Kurzrock R et al (2021) A phase 1b study to evaluate the safety and efficacy of durvalumab in combination with tremelimumab or danvatirsen in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk 21:309–317. https://doi.org/10.1016/j.clml.2020.12.012CrossRefPubMed

13.

Vafaei S, Zekiy AO, Khanamir RA, Zaman BA, Ghayourvahdat A, Azimizonuzi H, Zamani M (2022) Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier. Cancer Cell Int 22:2. https://doi.org/10.1186/s12935-021-02407-8CrossRefPubMedPubMedCentral

14.

Wu Q, Qian W, Sun X, Jiang S (2022) Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. J Hematol Oncol 15:143. https://doi.org/10.1186/s13045-022-01362-9CrossRefPubMedPubMedCentral

15.

Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D et al (2017) Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol 139:335-346.e3. https://doi.org/10.1016/j.jaci.2016.04.025CrossRefPubMed

16.

Lei Q, Wang D, Sun K, Wang L, Zhang Y (2020) Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors. Front Cell Dev Biol 8:672. https://doi.org/10.3389/fcell.2020.00672CrossRefPubMedPubMedCentral

17.

Mitsuiki N, Schwab C, Grimbacher B (2019) What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev 287:33–49. https://doi.org/10.1111/imr.12721CrossRefPubMed

18.

Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Gutiérrez EC et al (2022) Relatlimab and Nivolumab versus Nivolumab in untreated advanced melanoma. N Engl J Med 386:24–34. https://doi.org/10.1056/NEJMoa2109970CrossRefPubMedPubMedCentral

19.

Granito A, Marinelli S, Forgione A, Renzulli M, Benevento F, Piscaglia F, Tovoli F (2021) Regorafenib combined with other systemic therapies: exploring promising therapeutic combinations in HCC. J Hepatocell Carcinoma 8:477–492. https://doi.org/10.2147/jhc.s251729CrossRefPubMedPubMedCentral

20.

Hsu J, Hodgins JJ, Marathe M, Nicolai CJ, Bourgeois-Daigneault MC, Trevino TN et al (2018) Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Invest 128:4654–4668. https://doi.org/10.1172/jci99317CrossRefPubMedPubMedCentral

21.

Wagner AK, Kadri N, Tibbitt C, Vande Ven K, Bagawath-Singh S, Oliinyk D et al (2022) PD-1 expression on mouse intratumoral NK cells and its effects on NK cell phenotype. Science 25:105137. https://doi.org/10.1016/j.isci.2022.105137CrossRef

22.

Zhang X, Sabio E, Krishna C, Ma X, Wang J, Jiang H et al (2021) Qa-1b modulates resistance to Anti-PD-1 immune checkpoint blockade in tumors with defects in antigen processing. Mol Cancer Res 19:1076–1084. https://doi.org/10.1158/1541-7786.mcr-20-0652CrossRefPubMedPubMedCentral

23.

Gotthardt D, Putz EM, Straka E, Kudweis P, Biaggio M, Poli V et al (2014) Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance. Blood 124:2370–2379. https://doi.org/10.1182/blood-2014-03-564450CrossRefPubMed

24.

Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr (1975) Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35:2434–2439PubMed

25.

Griswold DP, Corbett TH (1975) A colon tumor model for anticancer agent evaluation. Cancer 36:2441–2444. https://doi.org/10.1002/1097-0142(197512)36:6%3C2441::aid-cncr2820360627%3E3.0.co;2-pCrossRefPubMed

26.

Muraoka D, Seo N, Hayashi T, Tahara Y, Fujii K, Tawara I et al (2019) Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistance. J Clin Invest 129:1278–1294. https://doi.org/10.1172/jci97642CrossRefPubMedPubMedCentral

27.

Kashima H, Momose F, Umehara H, Miyoshi N, Ogo N, Muraoka D et al (2016) Epirubicin, identified using a novel luciferase reporter assay for foxp3 inhibitors, inhibits regulatory t cell activity. PLoS One 11:e0156643. https://doi.org/10.1371/journal.pone.0156643CrossRefPubMedPubMedCentral

28.

Jin Y, An X, Mao B, Sun R, Kumari R, Chen X et al (2022) Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment. Sci Rep 12:3278. https://doi.org/10.1038/s41598-022-07153-zCrossRefPubMedPubMedCentral

29.

Wu J, Gao FX, Wang C, Qin M, Han F, Xu T et al (2019) IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma. J Exp Clin Cancer Res 38:321. https://doi.org/10.1186/s13046-019-1310-0CrossRefPubMedPubMedCentral

30.

Wagner AK, Wickström SL, Tallerico R, Salam S, Lakshmikanth T, Brauner H et al (2016) Retuning of mouse NK cells after interference with MHC class I sensing adjusts self-tolerance but preserves anticancer response. Cancer Immunol Res 4:113–123. https://doi.org/10.1158/2326-6066.cir-15-0001CrossRefPubMed

31.

Sanmamed MF, Chester C, Melero I, Kohrt H (2016) Defining the optimal murine models to investigate immune checkpoint blockers and their combination with other immunotherapies. Ann Oncol 27:1190–1198. https://doi.org/10.1093/annonc/mdw041CrossRefPubMed

32.

Taylor MA, Hughes AM, Walton J, Coenen-Stass AML, Magiera L, Mooney L et al (2019) Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery. J Immunother Cancer 7:328. https://doi.org/10.1186/s40425-019-0794-7CrossRefPubMedPubMedCentral

33.

Messenheimer DJ, Jensen SM, Afentoulis ME, Wegmann KW, Feng Z, Friedman DJ et al (2017) Timing of PD-1 blockade is critical to effective combination immunotherapy with anti-OX40. Clin Cancer Res 23:6165–6177. https://doi.org/10.1158/1078-0432.CCR-16-2677CrossRefPubMedPubMedCentral

34.

Nguyen HM, Bommareddy PK, Silk AW, Saha D (2021) Optimal timing of PD-1 blockade in combination with oncolytic virus therapy. Semin Cancer Biol 86:971–980. https://doi.org/10.1016/j.semcancer.2021.05.019CrossRefPubMed

35.

Shioya K, Matsumura T, Seki Y, Shimizu H, Nakamura T, Taniguchi S (2021) Potentiated antitumor effects of APS001F/5-FC combined with anti-PD-1 antibody in a CT26 syngeneic mouse model. Biosci Biotechnol Biochem 85:324–331. https://doi.org/10.1093/bbb/zbaa057CrossRefPubMed

36.

Chung YM, Khan PP, Wang H, Tsai WB, Qiao Y, Yu B et al (2021) Sensitizing tumors to anti-PD-1 therapy by promoting NK and CD8+ T cells via pharmacological activation of FOXO3. J Immunother Cancer 9:e002772. https://doi.org/10.1136/jitc-2021-002772CrossRefPubMedPubMedCentral

37.

Kärre K (1991) MHC gene control of the natural killer system at the level of the target and the host. Semin cancer biol 2(5):295–309PubMed

38.

Proia TA, Singh M, Woessner R, Carnevalli L, Bommakanti G, Magiera L et al (2020) STAT3 Antisense oligonucleotide remodels the suppressive tumor microenvironment to enhance immune activation in combination with anti-PD-L1. Clin Cancer Res 26:6335–6349. https://doi.org/10.1158/1078-0432.ccr-20-1066CrossRefPubMed

39.

Al Zaid Siddiquee K, Turkson J (2008) STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res 18:254–267. https://doi.org/10.1038/cr.2008.18CrossRefPubMed

40.

Grimaldi A, Cammarata I, Martire C, Focaccetti C, Piconese S, Buccilli M et al (2020) Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens. Commun Biol 3:85. https://doi.org/10.1038/s42003-020-0811-xCrossRefPubMedPubMedCentral

Titel: Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models
verfasst von: Hiroyuki Takahashi
Nao Miyoshi
Hisashi Murakami
Yuta Okamura
Naohisa Ogo
Akimitsu Takagi
Daisuke Muraoka
Akira Asai
Publikationsdatum: 05.04.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 7/2023
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-023-03440-4

Springer Medizin

Combined therapeutic effect of YHO-1701 with PD-1 blockade is dependent on natural killer cell activity in syngeneic mouse models

Abstract

Neu im Fachgebiet Onkologie

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

Viel pflanzliche Nahrung, seltener Prostata-Ca.-Progression

Alter verschlechtert Prognose bei Endometriumkarzinom

Darf man die Behandlung eines Neonazis ablehnen?

Update Onkologie

Springer Medizin

Abstract

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