Anti-PD-1 therapy triggers Tfh cell–dependent IL-4 release to boost CD8 T cell responses in tumor-draining lymph nodes

Abstract

Anti-PD-1 therapy targets intratumoral CD8+ T cells to promote clinical responses in cancer patients. Recent evidence suggests an additional activity in the periphery, but the underlying mechanism is unclear. Here, we show that anti-PD-1 mAb enhances CD8+ T cell responses in tumor-draining lymph nodes by stimulating cytokine production in follicular helper T cells (Tfh). In two different models, anti-PD-1 mAb increased the activation and proliferation of tumor-specific T cells in lymph nodes. Surprisingly, anti-PD-1 mAb did not primarily target CD8+ T cells but instead stimulated IL-4 production by Tfh cells, the major population bound by anti-PD-1 mAb. Blocking IL-4 or inhibiting the Tfh master transcription factor BCL6 abrogated anti-PD-1 mAb activity in lymph nodes while injection of IL-4 complexes was sufficient to recapitulate anti-PD-1 mAb activity. A similar mechanism was observed in a vaccine model. Finally, nivolumab also boosted human Tfh cells in humanized mice. We propose that Tfh cells and IL-4 play a key role in the peripheral activity of anti-PD-1 mAb.

Type II Interleukin-4 Receptor Activation in Basal Breast Cancer Cells Promotes Tumor Progression via Metabolic and Epigenetic Modulation

“…In the context of immune cells, IL4 signaling has been characterized as largely immunosuppressive and pro-tumorigenic, mediated by the previously discussed role it plays in polarizing tumor-associated macrophages to the M2 phenotype [56]. However, there is some evidence in the literature to suggest that IL4 signaling acting through CD8 lymphocytes expressing the type I IL4 receptor can boost anti-tumor immunity in the context of immune checkpoint blockade [57]. Here, we demonstrate that IL4 signaling acting on breast cancer cells through the type II receptor is mitogenic and supports the expression of pro-survival genes.…”

Mature tertiary lymphoid structures: important contributors to anti-tumor immune efficacy

“…Conversely, reductions in Tfh cell populations result in compromised TLS, diminished immune infiltration, and weakened tumor control; however, these features can be restored following the transfer of pathogen-specific CD4+ T cells ( 53 , 54 ). Tfh cells augment the effector function of CD8+ T cells through the secretion of IL-21 and IL-4, achieving a positive response to anti-PD-1 therapy ( 55 , 56 ). Collectively, these findings underscore the critical role of Tfh cells not only in facilitating GC reaction and B-cell response but also in promoting CD8+ T-cell response, thus highlighting their potential as a crucial factor in enhancing immunotherapy efficacy.…”