Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors

Our plain-English summary of Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors, by A.J. Currie, R.G. van der Most, S.A. Broomfield, et al (The Journal of Immunology, 2008).

The study

• Authors: A.J. Currie, R.G. van der Most, S.A. Broomfield, A.C. Prosser, M.G. Tovey, B.W. Robinson
• Journal: The Journal of Immunology
• Published: 2008;180(3):1535-44
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Effective antitumor CD8 T cell responses may be activated by directly targeting the innate immune system within tumors. We investigated this response by injecting a range of TLR agonists into established tumors using a mouse model of malignant mesothelioma stably transduced with the hemagglutinin (HA) gene as a marker Ag (AB1-HA). Persistent delivery of the dsRNA mimetic poly(I:C) into established AB1-HA tumors resulted in complete tumor resolution in 40% of mice, with the remaining mice also showing a significant delay in tumor progression. Experiments in athymic nude mice along with CD8 depletion and IFN-alphabeta blocking studies revealed that tumor resolution required both CD8 T cells and type I IFN induction, and was associated with local changes in MHC class I expression. Surprisingly, however, tumor resolution was not associated with systemic dissemination or tumor infiltration of effector CD8 T cells. Instead, the antitumor response was critically dependent on the reactivation of tumor-resident CD8 T cell responses. These studies suggest that, once reactivated, pre-existing local CD8 T cell responses are sufficient to resolve established tumors and that in situ type I IFN is a determining factor.

In plain English

This was a laboratory study in mice. It did not study people or asbestos exposure. The authors grew a mouse malignant mesothelioma cell line (AB1-HA, marked with an influenza protein) as tumors under the skin of female mice. They then injected substances that stimulate immune sensors called Toll-like receptors (TLRs) directly into the tumors. Agonists for TLR3, TLR7 and TLR9 slowed the growth of established tumors. Agonists for TLR2 and TLR4 had no effect on tumor growth. Six once-daily injections of poly(I:C), a TLR3 agonist, into smaller established tumors cured 40% of mice, and cured mice resisted the same tumor when it was injected again. No tumors resolved in athymic nude mice, which lack T cells. Removing CD8 T cells or blocking type I interferon (IFN-alpha/beta) also prevented resolution. A second, untreated tumor in the same mouse did not respond. Treated and untreated tumors held similar numbers of CD8 T cells. The authors concluded that local TLR treatment reactivated CD8 T cells already present in the tumor, and that this depended on type I interferon.

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 model)
• Who was studied: Female BALB/c wild-type and athymic nude mice, aged 6 to 8 weeks, implanted with the mouse mesothelioma cell line AB1-HA (AB1 transfected with influenza hemagglutinin); work done at the University of Western Australia, Perth
• Exposure: Not an asbestos exposure study. The 'exposure' was injection into the tumor of TLR agonists: Pam3Cys (TLR2), poly(I:C) (TLR3), LPS (TLR4), 3M-019 (TLR7) and CpG 1668 (TLR9). Further experiments focused on poly(I:C).
• Main results:
  • In mice with established (day 16) tumors, ligands for TLR3, TLR7 and TLR9 delayed tumor growth, with survival time increased by 25% as printed. TLR2 and TLR4 agonists had no effect on tumor growth.
  • Six once-daily poly(I:C) injections into smaller established (day 10) tumors resulted in complete cure in 40% of mice. Cured mice resisted rechallenge with the original tumor line.
  • In athymic nude mice, poly(I:C) produced no tumor resolution.
  • In wild-type mice, depleting CD8 T cells abolished poly(I:C)-induced tumor resolution. Depleting NK cells or CD4 T cells did not.
  • Neutralizing type I interferon (IFN-alpha/beta) prevented poly(I:C)-driven tumor resolution. Resolution was associated with increased MHC class I expression in the tumor.
  • In mice with two tumors on the same flank, the untreated second tumor did not respond when the first was treated with poly(I:C).
  • Poly(I:C) increased tumor-specific killing activity (CTL activity) in the lymph nodes draining the tumor. This activity was not found elsewhere.
  • Treated and untreated tumors contained similar numbers of CD8 T cells.
  • When CD8 T cells were depleted during the first 4 days after tumor implantation, later poly(I:C) treatment did not work.
  • In nude mice, CD8 T cells transferred from poly(I:C)-cured mice had no effect when given alone. Combined with poly(I:C), they increased survival time and led to some tumor resolution.
• The authors' conclusion: The authors concluded that local delivery of TLR agonists activated pre-existing tumor-sensitive CD8 T cells enough to produce antitumor responses. They concluded this was mediated by type I interferon induced by viral-type TLR ligands.
• Limitations the authors state:
  • Larger tumors were affected by treatment but did not regress. The authors suggest the pool of pre-existing CD8 T cells is limiting.
  • Too few target cells were recovered from tumors to measure tumor-specific killing inside the tumors.

Topics

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

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

Related studies

• Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation — A.J. Currie, A. Prosser, et al. (2009)
• Deliberately provoking local inflammation drives tumors to become their own protective vaccine site — C. Jackaman, A.M. Lew, et al. (2008)
• 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)
• Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity — W.J. Lesterhuis, J. Salmons, et al. (2013)
• Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma — G. Pasello, L. Urso, et al. (2014)
• Defect in recruiting effector memory CD8+ T-cells in malignant pleural effusions compared to normal pleural fluid — A. Scherpereel, B.D. Grigoriu, et al. (2013)

Browse more research in The Journal of Immunology, or return to medical research.