CD4⁺ T‐cell‐mediated anti‐tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis

Abstract

Previous reports have suggested that autoimmune sequelae may be an unavoidable consequence of successful immunization against tumor-associated antigens, which are typically non-mutated self-antigens. Using a melanoma model, we demonstrated that CD4 1 T-cell-mediated anti-tumor immunity and autoimmunity could be separated by modulating the STAT4/STAT6 signaling axis. Our results have revealed an unexpected dichotomy in the effector phase following cancer vaccination where anti-tumor immunity is mediated via a STAT6 and IL-4-dependent pathway, whereas autoimmune pathology is mediated via STAT4 through a mechanism that relies partially on IFN-c. Our results offer a possibility to elicit specific anti-tumor responses without triggering unwanted tissue autoimmune diseases.

Interactions Between the Immune System and Cancer: A Brief Review of Non-spatial Mathematical Models

“…New experimental results have suggested a more direct role for the CD4 + T cells (Mattes et al 2003;Perez-Diez et al 2007;Zhang et al 2009). In particular, these cells appear to have an effector role through the cytokines and chemokines that they produce (Mattes et al 2003;Zhang et al 2009). This means that CD4 + T cells can kill cancer cells even in the absence of CD8 + T cells and NK cells.…”

Selective Expansion of Chimeric Antigen Receptor-targeted T-cells with Potent Effector Function using Interleukin-4

“…Furthermore, IL-4 may antagonize tumor progression through local recruitment of neutrophils and eosinophils (25,26), dysregulation of stromal fibroblasts (27), and inhibition of angiogenesis (28). Reflecting this complexity, type 2 polarized tumor-infiltrating T-cells may either promote tumor rejection (22,29) or progression (20 -22), depending upon model system. Despite the intricate relationship between endogenous IL-4 and cancer, administration of supraphysiologic amounts of this cytokine has been widely tested as an experimental therapy for several malignancies.…”

Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma

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a b s t r a c tRecent experiments indicate that CD4 + Th2 cells can reject skin tumors in mice, while CD4 + Th1 cells cannot (Mattes et al, 2003;Zhang et al, 2009). These results are surprising because CD4 + Th1 cells are typically considered to be capable of tumor rejection.

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“…In this article, we investigate the surprising observation that Th2 cells, but not Th1 cells, are responsible for rejecting skin tumors produced by the widely used B16F10 melanoma cell line that grows in immune-competent mice (Mattes et al, 2003;Zhang et al, 2009). As a tool to make sense of these observed tumor-immune interactions, we used mathematical models.…”