Multiple Factors Determine the Oncolytic or Carcinogenic Effects of TLRs Activation in Cancer

Figure 10

Activation of TLR is a double-edged sword in cancer. Cancer cells can release TAAs to trigger innate immunity including DCs maturation, TLR activation, and induce trained immunity. Activation of innate immunity induces inflammation. Persistent inflammation promotes cellular transformation and carcinogenesis. Activation of TLR in DCs induce DC maturation and present the relevant TAA epitope to CD4⁺ T cells in the presence of MHC-II and costimulation factors CD40 and CD40L. Naïve CD4⁺ T cells thus are activated as Th1 cells. Th1 cells then assist in the activation of CD8⁺ T cells and its transformation into CTLs to exempt cancer cell killing. DCs are capable of presenting the TAA epitope to CD8⁺ T cells with MHC-1 in the presence of costimulation factors CD80/CD86 and CD28, i.e., cross-presentation. Cross-primed CD8⁺ T cells transform into CTLs and kill target cancer cells. However, activation of TLR in cancer cells induces increased expression of PD-L1, MMPs to facilitate cancer cell chemoresistance and metastasis. Cellular TLR activation from cancer cells also produces a variety of known and/or unknown factors to induce cancer stem cell proliferation, EMT transformation, and resistance to apoptosis. A number of immunosuppressor cells are also recruited and induced in the tumor microenvironment to prevent cancer cells from being eliminated by any immunological mechanism. Abbreviations: CTL, cytotoxic lymphocyte; DC, dendritic cell; EMT, epithelial-to-mesenchymal transition; MMP, matrix metalloproteinase; PD-L1, ligand of programed death 1; TAA, tumor-associated antigen; and TLR, toll-like receptor.