IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase

Our plain-English summary of IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase, by C. Jackaman, S. Lansley, J.E. Allan, et al (International Immunology, 2012).

The study

• Authors: C. Jackaman, S. Lansley, J.E. Allan, B.W. Robinson, D.J. Nelson
• Journal: International Immunology
• Published: 2012;24(6):357-68
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Murine and human mesothelioma tumors are susceptible to immunotherapy, particularly when immune adjuvants are delivered locally. We have shown that direct injection of IL-2 plus agonist anti-CD40 antibody induces regression of large mesothelioma tumors. These studies aimed to determine if NK cells contribute to IL-2/CD40 antibody-driven tumor eradication. We show that NK cells infiltrate developing mesothelioma tumors; however, their absence (in beige mice or in asialo GM(1) antibody-depleted C57BL/6J mice) does not alter tumor growth rates suggesting that they cannot function as effector cells in this microenvironment. Anti-CD40 antibody treatment did not alter the percent of NK cells in treated tumors or in draining lymph nodes (dLNs), and tumor resolution occurred in the absence of NK cells. However, a two-tumor model showed that NK cells contributed to CD40-driven systemic immunity leading to resolution of untreated distal tumors. IL-2 treatment led to increased proportions of NK cells in tumors and dLNs, and in the absence of NK cells, IL-2 lost its therapeutic effect. In contrast, the absence of NK cells did not reduce the anti-tumor activity of the IL-2/anti-CD40 antibody combination yet tumors recurred in NK-deficient mice and > 37% of tumor cell re-challenged mice were unable to provide protection, implying insufficient memory. Furthermore, untreated distal tumors in NK-depleted mice were less readily cured than in immunologically intact mice. These data show that NK cells infiltrate mesothelioma tumors, which, after local IL-2 and/or anti-CD40 antibody treatment, provide help for the acquisition and/or maintenance of systemic immunity and long-term effector/memory responses.

In plain English

This laboratory study in mice asked whether natural killer (NK) cells, a type of immune cell, help a local treatment clear mesothelioma tumors. The tumors came from a mouse cell line originally made by injecting mice with asbestos fibers of unnamed type. Tumors were injected with IL-2, an anti-CD40 antibody, or both. NK cells were found in tumors by day 7 of growth. Untreated tumors grew no differently in mice with impaired NK cells. In mice whose NK cells were reduced by 80 to 90% with an antibody, tumors grew slightly faster, but the difference was not statistically significant. In mice with impaired NK cells, each single treatment improved survival but produced no cures. The combined treatment still enhanced survival in 71% of these mice, compared with 92% of normal mice. Where NK cells were depleted or impaired, tumors more often came back after the combined treatment, and in depleted mice untreated distant tumors cleared less often. The authors concluded that local treatment recruits NK cell help for lasting body-wide immunity. They noted that how NK cells contribute needs further investigation.

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 (mice, subcutaneous mesothelioma tumor model)
• Who was studied: Female C57BL/6J mice, NK-impaired beige mice and beige heterozygous mice, aged 6 to 8 weeks, from the Animal Resources Centre, Perth, Australia; groups of about 4 to 10 mice per experiment
• Exposure: Mice were inoculated with AE17 mesothelioma cells, a cell line derived from C57BL/6J mice injected with asbestos fibers (fiber type not stated). Tumors were treated by injection into the tumor with IL-2, agonist anti-CD40 antibody, or both, three times per week for 2 weeks. NK cells were depleted with anti-asialo GM1 antibody in some mice.
• Main results:
  • Depletion of NK cells with the anti-asialo GM1 antibody was 80 to 90% effective. Beige mice have impaired NK activity but still have NK cells.
  • Putative NK cells were present in the mesothelioma tumors by day 7 of tumor growth, with decreasing proportions in larger tumors.
  • Tumor growth did not differ between normal, beige and beige heterozygous mice.
  • In NK-depleted C57BL/6J mice, tumor growth increased slightly, but the difference did not reach statistical significance.
  • By the sixth dose, tumors treated with IL-2 alone or with the combination contained significantly higher percentages of NK cells than PBS-treated tumors.
  • In beige mice, IL-2 or anti-CD40 antibody alone improved survival but produced no cures. The combination enhanced survival in 71% of beige mice, compared with 92% of C57BL/6J mice.
  • Two-tumor model, immunologically intact mice: untreated distant tumors regressed in 3/4 mice given anti-CD40 antibody and in 4/4 given the combination. NK-depleted mice: distant tumors completely regressed in 3/5 given anti-CD40 antibody and in 2/5 given the combination.
  • After the combination treatment, tumors recurred within 3 months in 4/14 NK-depleted mice and in 0/12 intact mice. When rechallenged with tumor cells, 9/9 intact mice were protected, compared with 5/8 NK-depleted mice.
  • After regression with the combination treatment, tumors recurred in 8/10 beige mice and 6/8 beige heterozygous mice (Table 1). Tumors never recurred in normal C57BL/6J mice, which were monitored for over 500 days.
• The authors' conclusion: The authors concluded that NK cells naturally present in the tumors do not affect mesothelioma development. They also concluded that local IL-2 and/or anti-CD40 antibody recruits NK cell help for acquiring and maintaining body-wide immunity and long-term effector/memory responses.
• Limitations the authors state:
  • The authors state that the mechanism by which NK cells contribute to clearing distant tumors is unclear and requires further investigation.
  • The authors state that further studies are needed to confirm the suggested roles of NKT cells.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy.

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• Asbestos and cancer: human natural killer cell activity is suppressed by asbestos fibers but can be restored by recombinant interleukin-2 — B.W. Robinson (1989)

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