Figure 1.

Interactions of the immune system with a whole cell vaccine approach (GM-CSF-secreting tumor cell vaccine as one example) and other immune modulating therapies for the treatment of cancer. A) GM-CSF is secreted by irradiated vaccine cells, which attract dendritic cells (DCs) to the site of antigen. The antigen is then taken up by the DCs for processing and presentation. DCs can also be stimulated by monoclonal antibodies (mAb) that bind to specific tumor antigens on the vaccine cell surface via their Fc receptor recognizing the Fc portion of the mAb. Vaccine cell lines can also be modified to secrete other cytokines, express co-stimulatory molecules that further activate DCs (such as CD40L) or express molecules that block inhibitory signals such as TGFβ (not shown). Toll-like receptor (TLR) agonists or immunomodulatory chemotherapic agents such as paclitaxel can also stimulate DCs through TLRs to upregulate co-stimulatory molecules, increase cytokine production, and enhance antigen processing and presentation. B) DCs process and present tumor antigen derived from the vaccinating cells to CD4⁺ and CD8⁺ T cells. Tumor antigen is presented in the form of peptide/MHC complexes on APCs; T cells bind this complex with their T cell receptor (TCR). Additional signals are required for stimulation of T cells which can be provided by activated DCs or agonist antibodies to co-stimulatory molecule receptors such as anti-CD40, anti-4-1BB, and anti-OX40. The activation and proliferation of tumor antigen-specific T cells can also be increased with the use of blocking antibodies to immune checkpoint molecules such as CTLA-4 and PD-1. C) APCs and T cells can be suppressed by inhibitory cytokines and molecules such as TGFβ and IL-10 secreted by suppressive immune cell populations like MDSC and Tregs. Chemotherapy (such as cyclophosphamide and gemcitibine) and radiation, when used at immunomodulatory doses, can be used to inhibit these populations. D) Tumor cell killing occurs when the TCR expressed on effector CD8⁺ T cells recognizes tumor antigens presented by MHC molecules on the surface of tumor cells. If activated efficiently, CD8⁺ T cells can work synergistically with traditional treatments such as chemotherapy, radiation therapy, or monoclonal antibodies to kill or inhibit tumor cells.