The Divergent Role of Co-receptors and Cytokines in the Immune Response to Cancer and Self

Abstract

The mammalian immune system has evolved over millennia to respond to countless biologic factors and environmental cues. This exquisite system has been shaped over time, to destroy hostile invaders all while sparing healthy surrounding tissue. The immune system is vital to survival, a fact that is readily apparent when immune components are mutated in human disease or mouse models. When immune components are lost, this balance can be distorted in both directions. Alterations to pro-inflammatory molecules, such as Tumor Necrosis Factor alpha (TNFα) can increase infection and cancer risk. Conversely, mutations in immunoregulatory pathways such as programmed death-1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have been associated with increased autoimmune disease incidence. This balance is uniquely apparent in the PD-1 pathway and CTLA4 pathways. Blockade of the PD-1 pathway can elicit potent anti-tumor responses, as evidenced by monoclonal antibody therapy Nivolumab and Pembrolizumab response rates, but also can unleash off-tissue pathology such as type one diabetes (T1D). T1D in these cancer patients is rapid and severe. This is perhaps not surprising, as Non Obese Diabetic (NOD) mice treated with anti-PD-1 or anti-PD-L1 therapy rapidly succumb to fulminant T1D. In common, CTLA4 blockade has been shown to halt tumor growth and even cure patients of metastatic cancer, however it has also unleashed potent autoimmune responses in the gut, brain, heart and eyes. Being able to better dissect these pathways, determine who will respond poorly to therapy and how these therapies can be maximized for tumor destruction, are key questions to be answered by the field of immunology. Complementary to the idea of blocking an inhibitory signal, positive signals are also used to invigorate the immune system. OX40, a TNF receptor family member, has been shown to be integral in provide co-stimulation to effector and naïve T-cells, and agonism through this receptor can cause potent anti-tumor effects. Interconnected and also important, the cytokine IL-12 has been shown to induce profound changes in T-cells, driving cytolytic T-cell programming, higher cytokine production, better tumor trafficking, proliferation and survival in the tumor environment while preventing tumor induced T-cell exhaustion. Like PD-1 and CTLA4, both OX40 and IL-12 are associated with their own unique set of autoimmune conditions. The focus of this chapter and this thesis as whole will be on these two immunoregulatory pathways, PD-1 and CTLA-4 as well as two immunostimulatory pathways OX40 and IL-12 and their relative importance in autoimmunity and cancer immunity.