Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells

Our plain-English summary of Antigen quality determines the efficiency of antitumor immune responses generated in the absence of regulatory T cells, by A.S. Bergot, A. Durgeau, B. Levacher, et al (Cancer Gene Therapy, 2010).

The study

• Authors: A.S. Bergot, A. Durgeau, B. Levacher, B.M. Colombo, J.L. Cohen, D. Klatzmann
• Journal: Cancer Gene Therapy
• Published: 2010;17(9):645-54
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The observation that depletion or inhibition of regulatory T cells (Tregs) unleashes efficient antitumor effector immune responses that can lead to tumor eradication in mice has opened new perspectives for the development of cancer immunotherapy. The quality and overall efficiency of the effector immune responses induced in the absence of Tregs seem to depend on multiple factors that determine the result of a battle involving effector T cells (Teffs), Tregs and tumor cells. In this study, we investigated the quality of tumor-associated antigens (TAAs) as one such factor. We show that the presence of a strong dominant antigen is required for the induction of effector responses capable of tumor eradication in the absence of Tregs. The sole addition of a dominant antigen on tumor cells does not change tumor growth in unmanipulated mice, but improves tumor eradication rate from a few to almost 100% in the absence of Tregs. This eradication can be shown to result from the recruitment and activation of specific Teffs recognizing this antigen. We also show that the presence of such dominant antigens has the side effect of restricting the breadth of the immune response to other TAAs, which could favor the generation of escape mutant by tumor editing. Taken together, our results highlight the potential, and some requirements for cancer immunotherapy based on Treg depletion. They also show that, ultimately, tumor fate depends on multiple factors that should all be taken into consideration for the design of more efficient immunotherapy.

In plain English

This was a laboratory experiment in mice testing whether the quality of a tumor antigen determines whether tumors are eradicated when regulatory T cells (Tregs) are removed. The authors used the asbestos-induced BALB/c AB1 mesothelioma and its AB1-HA derivative expressing influenza hemagglutinin (HA), plus the 4T1 mammary carcinoma and 4T1-HA. In untreated mice both AB1 and AB1-HA grew in all animals with similar kinetics. After a single injection of the anti-CD25 antibody PC61 to deplete Tregs, rejection was 85% for AB1-HA versus 10% for AB1 (Table 1 lists 83.3% and 16.7%, n=12 each). After Treg depletion and AB1-HA challenge, survival was 75% in normal mice and 0% in InsHA mice, which lack anti-HA effector T cells. In BALB/c mice, HA-specific T cells rose only in the draining lymph nodes of Treg-depleted AB1-HA-bearing mice; in InsHA mice they rose without depletion and were Tregs. With Tregs present, up to 9x10^6 naive HA-specific T cells only delayed AB1-HA growth, while antigen-experienced HA-specific cells rejected AB1-HA but not AB1. Mice cured of AB1 rejected 4T1 (100%, n=3), whereas AB1-HA-cured mice rarely did.

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 (mouse) tumor-transplant immunology experiment comparing tumor lines with and without an added antigen, with and without regulatory T-cell depletion
• Who was studied: Female BALB/c mice aged 6-8 weeks, plus InsHA and SFE TCR-HA transgenic mice bred in the authors' facility; tumor lines were the asbestos-induced BALB/c AB1 mesothelioma, AB1-HA, 4T1 mammary carcinoma and 4T1-HA (laboratory study, Paris, France)
• Exposure: Not an asbestos-exposure study: the variables were expression of the influenza hemagglutinin (HA) antigen by tumor cells and depletion of regulatory T cells by a single 125 mg intraperitoneal injection of the anti-CD25 antibody PC61; the AB1 line is described only as an asbestos-induced mesothelioma
• Main results:
  • In unmanipulated BALB/c mice, AB1 and AB1-HA tumors grew in all animals with similar kinetics
  • After Treg depletion with PC61, rejection was 85% for AB1-HA versus 10% for AB1
  • Among Treg-depleted mice challenged with AB1-HA, survival was 75% in normal (BALB/c) mice compared with 0% in InsHA mice, which lack anti-HA effector T cells (log-rank P = 0.0017 in the Figure 2a comparison)
  • In BALB/c mice, HA-specific T cells measured by TCR-specific quantitative PCR increased only in the draining lymph nodes of Treg-depleted mice bearing AB1-HA tumors
  • In InsHA mice, where HA is a self-antigen, HA-specific T cells increased in the draining lymph nodes of AB1-HA-bearing mice and this detection was abolished by PC61 treatment, which the authors interpreted as recruitment of self-antigen-specific Tregs
  • With Tregs present, transfer of up to 9x10^6 naive HA-specific T cells delayed tumor growth and prolonged survival but produced no rejection, whereas antigen-experienced HA-specific T cells rejected AB1-HA but not AB1
  • On rechallenge of AB1-HA-cured, Treg-depleted mice: 100% rejected AB1-HA, 66% rejected AB1, 33% rejected 4T1-HA and 0% rejected 4T1; mice cured of AB1 rejected 4T1 in 100% of cases (n = 3)
  • After three successive AB1-HA challenges, all surviving mice rejected a subsequent 4T1 challenge
• The authors' conclusion: The authors concluded that expression of a potent dominant tumor antigen is key to effector responses able to eradicate tumors once Tregs are removed, that such a dominant antigen narrows the response to other tumor antigens, and that Treg manipulation should become an almost mandatory part of multimodal cancer immunotherapy
• Limitations the authors state:
  • The authors stated that antigen quality is not the only determinant of tumor fate, the outcome being multiparametric and uncertain even in genetically identical mice
  • The authors stated that further analyses would be needed to substantiate that tumor escape variants actually arise
  • The authors anticipated that such strategies would improve clinical responses only in a fraction of patients, given heterogeneity of tumor fate even in inbred mice

Topics

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

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

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