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. 2022 Sep 9;13:972021. doi: 10.3389/fimmu.2022.972021

Figure 1.

Figure 1

Mechanisms of CD4+ T cells as effectors of antitumor immunity independent of CD8+ T cells. Professional antigen-presenting cells (APCs), like activated dendritic cells (DCs, yellow), in the tumor microenvironment (TME) take up tumor antigens. Starting on the left-hand side of the figure, activated DCs present antigens to CD4+ T cells via MHC-II, in turn activating CD4+ T cells to secrete cytokines like IFNγ, TNFα, and IL-2 that activate effector CD8+ T cells (not shown here). Additionally, IFNγ from activated CD4+ T cells can act on tumor cells (gold) or stromal cells (grey) to increase the expression of monokine induced by IFNγ (Mig) and interferon-gamma-induced protein 10 (IP-10), causing inhibition of tumor angiogenesis and thus contributing to tumor cell death. Another possibility is that CD4+ T cells can contribute to tumor vessel normalization (not shown here). Activated DCs also secrete IL-12, stimulating CD4+ T cells to secrete more IFNγ which can feed back to activate more DCs, setting up a reciprocal interaction that further amplifies the immune cell activation cascade in the TME. Activated CD4+ T cells that differentiate into the Th1 subtype also release IFNγ that activates macrophages (blue) to an M1 phenotype through upregulation of inducible nitric oxide synthase (iNOS). Nitric oxide (NO) secreted by these M1 macrophages in the TME causes apoptosis of tumor cells. Finally, activated APCs, including DCs, may also stimulate the development of cytotoxic CD4+ T cell subsets. These cytotoxic CD4+ T cells may attack the tumor through two mechanisms. They may directly recognize MHC-II-positive tumor cells via their T-cell receptor and use contact-mediated delivery to release perforin (Prf) and granzyme B (GrB) to cause tumor cell death. Alternatively, cytotoxic CD4+ T cells may potentially recognize tumor cells in an MHC-independent fashion (like NK cells do) and use other activating receptors to identify activating ligands for those receptors that are selectively expressed by tumor cells to enable contact-mediated release of Prf and GrB into the tumor cells to eliminate MHC-deficient tumor cells through an MHC-independent mechanism. The ongoing tumor cell death from all these synergistic mechanisms may drive further antigen uptake by APCs and the development of a more robust antitumor immune response in the TME.