Integrating conventional and antibody-based targeted anticancer treatment into immunotherapy

Abstract

In advanced cancer, current conventional therapies or immunotherapies cannot eradicate all tumor cells for most patients. Integration of these two treatments for synergistic effects could eradicate more tumor cells and increase the overall survival rates. However, since how conventional treatments impact on immune system remains unclear, proper integration is still a challenge. Intensive chemo/radiotherapy may impair ongoing immune responses, while lower intensity of therapy might not kill enough tumor cells, both leading to tumor relapse. Current understanding of mechanisms of resistance to conventional and targeted cancer therapies has focused on cell intrinsic pathways that trigger DNA damage/repair or signaling pathways related to cell growth. Recent reports show that host T cells properly primed against tumor-specific antigens after conventional treatment, which can integrate with direct cytotoxic effects induced by radiation or chemotherapy to profoundly control tumors. Following cytotoxic anticancer treatment, tumor-derived DAMPs (damage-associated molecular patterns) can be sensed by innate cells, which drives type I interferon production for cross-priming of CD8⁺ T cells. Some types and protocols of chemotherapy or radiation can increase tumor-infiltrating lymphocytes that overcome resistance to immunotherapy. As such, a deeper understanding of the immune mechanisms of conventional and targeted cancer therapies will lead toward novel combinatorial anticancer strategies with improved clinical benefit.

Figure 1. Irradiation mediated sensing of tumor-derived DNA for induction of type I interferons (IFNs) in antigen-presenting cells (APCs)

Radiation results in the release of “find-me” and “eat-me” signals from tumor cells. During phagocytosis in myeloid cells, the DNA fragments hidden in irradiated tumor cells are released from phagosomes to cytoplasm, acting as a danger signal. The cGAS binds this DNA and generates cGAMP as a second messenger. cGAMP binds to STING, which subsequently activates IFN regulatory factor 3 (IRF3) or IRF7 to induce type I IFN production. Alternatively, DNA released from dying tumor cells can theoretically activate endosomal TLR9 and induce type I IFN production through Myd88.

Figure 2. Damage-associated molecular patterns (DAMPs) for innate immune activation in response to chemotherapy-induced tumor cell stress or death

Increased exposure of calreticulin on the surface of tumor cells facilitates their uptake through interaction with CD91 on antigen-presenting cells such as macrophage. Tumor released nucleic acid and high-mobility group box 1 protein (HMGB1) may bind to Toll-like receptors on antigen-presenting cells, which can subsequently increase antigen processing and induce maturation of dendritic cells. ATP secreted from dying tumor cells can bind to the P2X purinoceptor 7 receptor (P2X7R) of APCs, which resulting in production of IL-1β and chemotactic attraction of antigen-presenting cells.

Figure 3. The immune aspects of antibody-based targeted therapy

The effects of antibody-based targeted therapies on immune response include (1) FcRγ-dependent natural killer (NK) cell cytotoxicity and macrophage phagocytosis; (2) promoting dendritic cell (DC) priming and increasing the expression of co-stimulatory molecules, such as CD40, CD80, and CD86on the DC surface;(3) activating CD8⁺ T cells-dependent adaptive anti-tumor immunity.