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

Our plain-English summary of Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner, by C.M. Tilsed, M.L.O. Morales, R.M. Zemek, et al (BMC Cancer, 2024).

The study

• Authors: C.M. Tilsed, M.L.O. Morales, R.M. Zemek, B.A. Gordon, M.J. Piggott, A.K. Nowak, S.A. Fisher, R.A. Lake, W.J. Lesterhuis
• Journal: BMC Cancer
• Published: 2024;24(1):203
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2024. The Author(s).

In plain English

This was a laboratory study in mice and cultured tumor cells. It did not study asbestos exposure, but two of its tumor models were murine mesothelioma (AB1-HA and AE17). The authors used gene expression data from an earlier study of mouse tumors that did or did not respond to the chemotherapy drug cyclophosphamide. Their analysis ranked tretinoin, a vitamin A derivative, as the top drug predicted to make tumors responsive. In mice with AB1-HA mesothelioma, adding tretinoin to cyclophosphamide significantly increased survival (p = 0.0052) and raised the complete response rate from 0 to 50%. The benefit depended on T cells. In one experiment, 6/10 mice with intact immune systems were cured, compared with 1/10 mice depleted of CD4+ T cells and 0/5 depleted of CD8+ T cells. In the lab dish, tretinoin did not make AB1-HA cells more sensitive to cyclophosphamide-related compounds. In colon carcinoma, sarcoma, breast cancer, Lewis lung carcinoma and AE17 mesothelioma models, tretinoin added no benefit. The authors concluded that moving the combination into the clinic appears premature.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse tumor models), with in vitro cell assays and analysis of tumor gene expression data
• Who was studied: Male or female 8 to 10 week-old BALB/cArc or C57BL/6 mice injected under the skin with tumor cell lines: AB1-HA and AE17 murine mesothelioma, CT26 colon carcinoma, WEHI164 sarcoma, 4T1 breast cancer and Lewis lung carcinoma. Most groups had 5 or 10 mice. Western Australia.
• Exposure: No asbestos exposure was studied. Mice were treated with tretinoin at 10 mg/kg into the abdomen, starting 3 days before cyclophosphamide, for 9 doses in total. Cyclophosphamide was given at 200 mg/kg.
• Main results:
  • In the gene expression analysis of cyclophosphamide responders, tretinoin was the top predicted upstream regulator of a cyclophosphamide-sensitive tumor environment.
  • In mice with AB1-HA mesothelioma (n = 10 per group), adding tretinoin significantly increased survival after cyclophosphamide (p = 0.0052).
  • In the AB1-HA mice, the complete response rate rose from 0 to 50% with the combination.
  • In the AB1-HA mice, the combination was well tolerated, with no additional weight loss compared with cyclophosphamide alone.
  • In AB1-HA mice receiving the combination, 6/10 mice with intact immune systems were cured. Only 1/10 mice depleted of CD4+ T cells were cured (p = 0.003), and 0/5 mice depleted of CD8+ T cells were cured (p less than 0.0001).
  • Genes switched on by tretinoin were enriched in tumors that fully responded to cyclophosphamide, compared with tumors that kept growing.
  • In AB1-HA cells in the lab, adding tretinoin did not significantly change the dose needed to kill cells for acrolein (p = 0.56) or mafosfamide (p = 0.27).
  • In mice with CT26 colon carcinoma, WEHI164 sarcoma, 4T1 breast cancer, AE17 murine mesothelioma or Lewis lung carcinoma, adding tretinoin to cyclophosphamide had no effect on survival or tumor growth.
  • Compared with all the other tumor types, AB1-HA tumors expressed lower levels of RAR alpha, RAR gamma, RXR alpha and RXR beta, and higher levels only of RAR beta and RXR gamma.
  • AB1-HA tumors had lower expression of inflammatory genes than AE17 and CT26. The authors took this to suggest that an inflamed tumor environment before treatment is not what drives the sensitivity.
• The authors' conclusion: The authors concluded that, given the high variability in efficacy between tumor models and no clear underlying mechanism, translation of tretinoin plus cyclophosphamide into the clinic appears premature at this stage.
• Limitations the authors state:
  • The data used to pick the drug came from the AB1-HA model alone, and the authors note the limits of predicting drug combinations from a single tumor model.
  • Because the RNA data came from whole tumors, the authors could not tell which cells express each retinoic acid receptor.
  • The authors found no clear mechanism to explain why the combination worked in one model and not the others.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Tumor Microenvironment, Mesothelioma.

Related studies

• Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth — R.G. van der Most, A.J. Currie, et al. (2009)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)
• Voluntary exercise in mesothelioma: effects on tumour growth and treatment response in a murine model — S.A. Fisher, C.J. Peddle-McIntyre, et al. (2020)
• Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity — W.J. Lesterhuis, J. Salmons, et al. (2013)
• All-trans-retinoic acid inhibits tumour growth of malignant pleural mesothelioma in mice — C. Tabata, R. Tabata, et al. (2009)
• Geldanamycin treatment does not result in anti-cancer activity in a preclinical model of orthotopic mesothelioma — M.L. Orozco Morales, C.A. Rinaldi, et al. (2023)

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