How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies

Abstract

Aiming to get a better insight on the impact of regulatory CD25+CD4+ T cells in tumor-immunobiology, a simple mathematical model was previously formulated and studied. This model predicts the existence of two alternative modes of uncontrolled tumor growth, which differ on their coupling with the immune system, providing a plausible explanation to the observation that the development of some tumors expand regulatory T cells whereas others do not. We report now the study of how these two tumor classes respond to different therapies, namely vaccination, immune suppression, surgery, and their different combinations. We show 1) how the timing and the dose applied in each particular treatment determine whether the tumor will be rejected, with or without concomitant autoimmunity, or whether it will continue progressing with slower or faster pace; 2) that both regulatory T cell-dependent and independent tumors are equally sensitive to vaccination, although the former are more sensitive to T cell depletion treatments and are unresponsive to partial surgery alone; 3) that surgery, suppression, and vaccination treatments, can synergistically improve their individual effects, when properly combined. Particularly, we predict rational combinations helping to overcome the limitation of these individual treatments on the late stage of tumor development.

Resveratrol analogue HS-1793 induces the modulation of tumor-derived T cells

“…One of the most potent and well-studied suppressive phenotypes found in the tumor microenvironment is the regulatory subpopulation among CD4 + cells (Treg cells), constitutively expressing high levels of CD25, CTLA-4, GITR and Foxp3, displaying anergy when stimulated by T-cell receptor cross-linking in vitro, and actively inhibiting CD4 + CD25 -T cells, CD8 + manner (6,7). Increasing evidence shows that Treg cells play an important role in immune evasion mechanisms employed by cancer (8)(9)(10). Tumors may differentiate, expand, recruit and activate Treg (tumor Treg) cells via multiple mechanisms and potently abrogate antitumor immunity (11).…”

A model for effects of adaptive immunity on tumor response to chemotherapy and chemoimmunotherapy

“…This model did not include immunosuppressive effects or Tregs, and thus the beneficial reduction of the Treg population was not accounted for along with the reduction in effector T cells. Several studies by Leon et al [82,83] The model presented in this study has several limitations. The innate immune system was not included, even though it can be an important part of the host anti-tumor response.…”

Emergent Group Dynamics Governed by Regulatory Cells Produce a Robust Primary T Cell Response

“…Several other mathematical models have been developed for naturally occurring regulatory T cells (Burroughs et al, 2006; Carneiro et al, 2005; León et al, 2000, 2001, 2003, 2004, 2007a, 2007b) and adaptive regulatory T cells (Fouchet and Regoes, 2008), but these papers focus on the function of regulatory T cells in inducing and maintaining immune tolerance to certain targets. In this paper, we do not address how regulatory T cells induce tolerance, but in how they govern the dynamics of a primary immune response against infection.…”