Deliberately provoking local inflammation drives tumors to become their own protective vaccine site

Our plain-English summary of Deliberately provoking local inflammation drives tumors to become their own protective vaccine site, by C. Jackaman, A.M. Lew, Y. Zhan, et al (International Immunology, 2008).

The study

• Authors: C. Jackaman, A.M. Lew, Y. Zhan, J.E. Allan, B. Koloska, P.T. Graham, B.W. Robinson, D.J. Nelson
• Journal: International Immunology
• Published: 2008;20(11):1467-79
• Cited by: 60 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Anti-cancer immunotherapies aim to generate resolution of all existing tumors, including inaccessible ones, and provide long-term protection against recurrence. This is rarely achieved. Thus, we aimed to determine if the tumor microenvironment could be turned into a potent 'self'-vaccine site. Our target was to eradicate larger tumor burdens. Our models respond to single-agent immunotherapies; however, they fail at a precisely defined 'cut-off' tumor burden. Thus, this system was used to define the immune mechanisms required to mediate regression of larger tumors that are resistant to mono-immunotherapies. We report that direct injection of IL-2 with agonist anti-CD40 antibody into the tumor bed resulted in permanent resolution of treated and untreated distal tumors. Tumor-infiltrating CD8(+) T cells and neutrophils collaborated to eradicate treated tumors, IFNgamma was not critical and protective memory was preserved. This approach relied only on tumor antigens expressed within the tumor microenvironment. It also avoided systemic toxicities, did not require chemotherapy or surgery and is clinically useful because only one tumor site has to be accessible for treatment. We conclude that provoking intra-tumoral inflammation skews the tumor microenvironment from tumorigenic to immunogenic, resulting in the resolution of treated and untreated distal tumors, as well long-term protective memory.

In plain English

This was a laboratory experiment in mice testing an immune treatment for malignant mesothelioma (MM). It was not a study of asbestos exposure in people. The main tumor cell line, AE17, came from mice injected with asbestos fibers; the article does not name the fiber type. Tumors were grown under the skin. The authors injected IL-2, an agonist anti-CD40 antibody, or both directly into tumors. Given into the bloodstream, the combination caused toxic deaths and no tumors resolved. Injected into small tumors, IL-2 alone cleared tumors in 83% of mice, anti-CD40 alone in 69%, and the combination in 100%. In larger tumors only the combination worked, with complete regression in 87% of mice. Cured mice given new tumor cells later developed no tumors. The combination also cleared a second, untreated tumor in 100% of mice whose treated tumor was small and in 80% whose treated tumor was large. Removing immune cells suggested CD8+ T cells and neutrophils were both needed against large tumors. The authors concluded that provoking inflammation inside a tumor let it act as its own vaccine site.

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 treatment study)
• Who was studied: Female C57BL/6J, BALB/c and nude mice aged 6 to 8 weeks from the Animal Resources Center, Perth, Australia, plus GK and GK/perforin-deficient mice bred at the Walter and Eliza Hall Institute. Tumors were grown under the skin from the AE17 and AB1 mesothelioma cell lines and the Lewis lung carcinoma line. Group sizes were mostly 4 to 20 mice per group. Study dates are not given.
• Exposure: The AE17 mesothelioma cell line came from the peritoneal cavity of mice injected with asbestos fibers; the fiber type is not specified. The treatments studied were IL-2 (20 µg per dose) and agonist anti-CD40 antibody (40 µg per dose), alone or combined. They were injected directly into tumors three times a week for 2 weeks, and in comparison experiments were given into the bloodstream.
• Main results:
  • Given into the bloodstream, combined IL-2 and anti-CD40 caused a high death rate, with 50% of deaths related to toxicity, and no tumors resolved.
  • In small AE17 tumors, anti-CD40 injected into the tumor led to complete regression in 69% of mice for more than 1 year.
  • In small AE17 tumors, IL-2 alone injected into the tumor led to complete regression in 83% of mice.
  • In small AE17 tumors, the combination led to complete regression in 100% of mice.
  • In larger AE17 tumors (over 25 mm2), neither monotherapy cured any mice. The combination produced complete regression in 87% of mice.
  • Cured mice that were re-challenged with AE17 tumor cells after more than a year did not develop tumors.
  • In mice with two tumors, the combination injected into one tumor eradicated the untreated distal tumor in 100% of animals with small treated tumors and in 80% of animals with large treated tumors. In a further experiment with two large tumors, 83% of the untreated large tumors completely regressed.
  • When CD8+ cells were depleted, the combination no longer restrained large tumor growth in 70% of animals. The authors stated that CD8+ cells are critical for eradicating large but not small tumors.
  • When neutrophils (PMN) were depleted during combination treatment, anti-tumor immunity was completely abolished.
  • With IFN-gamma blocked, the combination still permanently cured more than 80% of mice, regardless of tumor size when treatment began.
  • When NK cells were removed, the combination's cure rate in large tumors fell from 90 to 65%, which was not statistically significant.
  • In other models, the combination eradicated small and large AB1 mesothelioma tumors in 83% of BALB/c mice. In Lewis lung carcinoma it produced regression in 70% of mice, with 29% permanently cured (40% with extended treatment).
• The authors' conclusion: The authors concluded that injecting IL-2 with anti-CD40 antibody into the tumor provoked local inflammation that turned the tumor into its own vaccine site. In their mice, this led to regression of treated and untreated distal tumors, with protective memory retained. They also concluded that eradicating large tumors required both CD8+ cells and neutrophils.
• Limitations the authors state:
  • The authors stated it is very difficult to assess how well IFN-gamma was actually blocked.
  • The authors acknowledged that applying the two-tumor model to metastases may be an over-interpretation.
  • The authors had not identified how the T cells and neutrophils work together.

Topics

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

Related studies

• WT1 peptide vaccinations induce CD4 and CD8 T cell immune responses in patients with mesothelioma and non-small cell lung cancer — L.M. Krug, T. Dao, et al. (2010)
• Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells — C. Jackaman, S. Cornwall, et al. (2009)
• IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase — C. Jackaman, S. Lansley, et al. (2012)
• Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors — A.J. Currie, R.G. van der Most, et al. (2008)
• Intratumoral macrophage phenotype and CD8+ T lymphocytes as potential tools to predict local tumor outgrowth at the intervention site in malignant pleural mesothelioma — R. Cornelissen, L.A. Lievense, et al. (2015)
• 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)

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