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BMC Cancer
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Cytostatic Therapy | Research

Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner

Authors: Caitlin M. Tilsed, M. Lizeth Orozco Morales, Rachael M. Zemek, Brianna A. Gordon, Matthew J. Piggott, Anna K. Nowak, Scott A. Fisher, Richard A. Lake, W. Joost Lesterhuis

Published in: BMC Cancer | Issue 1/2024

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Abstract

Background

Chemotherapy is included in treatment regimens for many solid cancers, but when administered as a single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.

Methods

We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models.

Results

The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pre-treatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was model-selective, and could not be replicated using other cell lines.

Conclusions

Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.
Appendix
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Literature
1.
2.
3.
Motzer RJ, et al. Nivolumab for metastatic renal cell carcinoma: results of a Randomized Phase II Trial. J Clin Oncol. 2015;33:1430–7.PubMedCrossRef
4.
Paz-Ares L, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22:198–211.PubMedCrossRef
5.
Paz-Ares L, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394:1929–39.PubMedCrossRef
6.
Michot JM, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.PubMedCrossRef
7.
Champiat S, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018;15:748–62.PubMedCrossRef
8.
Tilsed CM, et al. CD4 + T cells drive an inflammatory, TNF-α/IFN-rich tumor microenvironment responsive to chemotherapy. Cell Rep. 2022;41:111874.PubMedCrossRef
9.
10.
11.
Lesterhuis WJ, et al. Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations. Sci Rep. 2015;5:1–11.CrossRef
12.
Tilsed CM, et al. Retinoic acid induces an IFN-Driven Inflammatory Tumour Microenvironment, sensitizing to Immune Checkpoint Therapy. Front Oncol. 2022;12:849793.PubMedPubMedCentralCrossRef
13.
14.
Tang X-H, Gudas LJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011;6:345–64.PubMedCrossRef
15.
Jiménez-Lara AM, Clarke N, Altucci L, Gronemeyer H. Retinoic-acid-induced apoptosis in leukemia cells. Trends Mol Med. 2004;10:508–15.PubMedCrossRef
16.
Lee MO, Han SY, Jiang S, Park JH, Kim SJ. Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor beta. Biochem Pharmacol. 2000;59:485–96.PubMedCrossRef
17.
Yin W, Song Y, Liu Q, Wu Y, He R. Topical treatment of all-trans retinoic acid inhibits murine melanoma partly by promoting CD8 + T-cell immunity. Immunology. 2017;152:287–97.PubMedPubMedCentralCrossRef
18.
Bhattacharya N, et al. Normalizing Microbiota-Induced Retinoic Acid Deficiency stimulates protective CD8(+) T cell-mediated immunity in Colorectal Cancer. Immunity. 2016;45:641–55.PubMedPubMedCentralCrossRef
19.
Iland HJ, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012;120:1570–80. quiz 1752.PubMedCrossRef
20.
21.
Arrieta O, et al. Randomized phase II trial of all-trans-retinoic acid with chemotherapy based on paclitaxel and cisplatin as first-line treatment in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:3463–71.PubMedCrossRef
22.
23.
Bryan M, et al. A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (taxol) in patients with recurrent or metastatic breast cancer. Invest New Drugs. 2011;29:1482–7.PubMedCrossRef
24.
25.
Mirza N, et al. All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res. 2006;66:9299–307.PubMedPubMedCentralCrossRef
26.
Iclozan C, Antonia S, Chiappori A, Chen D-T, Gabrilovich D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother. 2013;62:909–18.PubMedPubMedCentralCrossRef
27.
Sun C-M, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204:1775–85.PubMedPubMedCentralCrossRef
28.
Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204:1765–74.PubMedPubMedCentralCrossRef
29.
Hall JA, et al. Essential role for retinoic acid in the Promotion of CD4 + T cell effector responses via retinoic acid receptor alpha. Immunity. 2011;34:435–47.PubMedPubMedCentralCrossRef
30.
31.
Guo Y, et al. A retinoic acid–rich tumor microenvironment provides clonal survival cues for tumor-specific CD8(+) T cells. Cancer Res. 2012;72:5230–9.PubMedPubMedCentralCrossRef
32.
Guo Y, et al. Dissecting the role of retinoic acid receptor isoforms in the CD8 response to infection. J Immunol. 2014;192:3336–44.PubMedCrossRef
33.
Bray NL, Pimentel H, Melsted P, Pachter L. Near-optimal probabilistic RNA-seq quantification. Nat Biotechnol. 2016;34:525–7.PubMedCrossRef
34.
35.
Krämer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.PubMedCrossRef
36.
Orozco Morales ML, et al. PPARα and PPARγ activation is associated with pleural mesothelioma invasion but therapeutic inhibition is ineffective. iScience. 2021;25:103571.PubMedPubMedCentralCrossRefADS
37.
38.
Subramanian A, Kuehn H, Gould J, Tamayo P, Mesirov J. P. GSEA-P: a desktop application for Gene Set Enrichment Analysis. Bioinformatics. 2007;23:3251–3.PubMedCrossRef
39.
Kang SG, Park J, Cho JY, Ulrich B, Kim CH. Complementary roles of retinoic acid and TGF-β1 in coordinated expression of mucosal integrins by T cells. Mucosal Immunol. 2011;4:66–82.PubMedCrossRef
40.
41.
Yoshihara K, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.PubMedCrossRefADS
42.
Moreb JS, et al. Retinoic acid down-regulates aldehyde dehydrogenase and increases cytotoxicity of 4-hydroperoxycyclophosphamide and acetaldehyde. J Pharmacol Exp Ther. 2005;312:339–45.PubMedCrossRef
43.
Kalemkerian GP, Ou X. Activity of fenretinide plus chemotherapeutic agents in small-cell lung cancer cell lines. Cancer Chemother Pharmacol. 1999;43:145–50.PubMedCrossRef
44.
Caliaro MJ, et al. Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines. Br J Cancer. 1997;75:333–40.PubMedPubMedCentralCrossRef
45.
Mazur L, Opydo-Chanek M, Stojak M, Wojcieszek K. Mafosfamide as a new anticancer agent: preclinical investigations and clinical trials. Anticancer Res. 2012;32:2783–9.PubMed
46.
Radojcic V, et al. Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination. Cancer Immunol Immunother. 2010;59:137–48.PubMedCrossRef
47.
van der Most RG et al. Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth. PLoS ONE 4, e6982 (2009).
48.
Tilsed CM, Fisher SA, Nowak AK, Lake RA, Lesterhuis WJ. Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action. Front Oncol. 2022;12:960317.PubMedPubMedCentralCrossRef
49.
Nowak AK, et al. Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety run-in. Lancet Oncol. 2020;21:1213–23.PubMedCrossRef
50.
Shalinsky DR, et al. Retinoid-induced suppression of squamous cell differentiation in human oral squamous cell carcinoma xenografts (line 1483) in athymic nude mice. Cancer Res. 1995;55:3183–91.PubMed
51.
Mosely SIS, et al. Rational selection of Syngeneic Preclinical Tumor models for Immunotherapeutic Drug Discovery. Cancer Immunol Res. 2017;5:29–41.PubMedCrossRef
52.
Georgiev P, et al. Reverse translating Molecular determinants of Anti-programmed Death 1 Immunotherapy response in mouse syngeneic tumor models. Mol Cancer Ther. 2022;21:427–39.PubMedPubMedCentralCrossRef
53.
Zemek RM, et al. Bilateral murine tumor models for characterizing the response to immune checkpoint blockade. Nat Protoc. 2020;15:1628–48.PubMedCrossRef
54.
Palomares T, García-Alonso I, San Isidro R, Méndez J, Alonso-Varona A. All-trans-retinoic acid counteract the tumor-stimulating effect of hepatectomy and increases survival of rats bearing liver metastases. J Surg Res. 2014;188:143–51.PubMedCrossRef
55.
Song X, et al. A tritherapy combination of a fusion protein vaccine with immune-modulating doses of sequential chemotherapies in an optimized regimen completely eradicates large tumors in mice. Int J Cancer. 2011;128:1129–38.PubMedCrossRef
56.
Carapuça EF, et al. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. J Pathol. 2016;239:286–96.PubMedPubMedCentralCrossRef
57.
Michael A, Hill M, Maraveyas A, Dalgleish A, Lofts F. 13-cis-retinoic acid in combination with gemcitabine in the treatment of locally advanced and metastatic pancreatic cancer–report of a pilot phase II study. Clin Oncol (R Coll Radiol). 2007;19:150–3.PubMedCrossRef
58.
Sacks PG, Harris D, Chou TC. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: a rationale for combination therapy with chemotherapeutic agents. Int J Cancer. 1995;61:409–15.PubMedCrossRef
59.
Grunt TW et al. null Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells. Br J Cancer 78, 79–87 (1998).
60.
Yan Y, et al. All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complement Altern Med. 2016;16:113.PubMedPubMedCentralCrossRef
61.
West AC, et al. An intact immune system is required for the anticancer activities of histone deacetylase inhibitors. Cancer Res. 2013;73:7265–76.PubMedCrossRef
62.
63.
Zemek RM, et al. Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment. Sci Transl Med. 2019;11:eaav7816.PubMedCrossRef
Metadata
Title
Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner
Authors
Caitlin M. Tilsed
M. Lizeth Orozco Morales
Rachael M. Zemek
Brianna A. Gordon
Matthew J. Piggott
Anna K. Nowak
Scott A. Fisher
Richard A. Lake
W. Joost Lesterhuis
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-11915-5

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