Systems Biology Analysis to Optimize Cancer Vaccination Therapies

Introduction: Initiation of an immune response requires activation of one or more naïve T cells. Each naïve T cell has a unique T cell receptor, and these cells traffic through the blood and lymphatic vasculatures, visiting each of the ~500 lymph nodes (LNs) in search of matching antigen. If a match is made, then the naïve T cell activates and proliferates. The resulting effector T cells enter the blood circulation to find and eradicate the source of antigen. Similar to pathogens like viruses, tumors can also create antigens that accumulate in lymph nodes, where they can induce activation of T cells. However, some tumors produce little antigen and cannot stimulate nT cell activation in the LNs. In addition, some cancers may have a high level of antigen, but activation is inhibited, especially tumor draining LNs (TDLNs) through mechanisms that are still unknown. We hypothesize that inhibition is due to accumulation of cancer-produced soluble factors. Cancer vaccines have the potential to address these deficiencies by providing additional cancer antigens and immune stimulating adjuvants. Here, we explore how the levels of antigen and putative suppressive factor in LNs affect the response to immunotherapy and cancer vaccination. This study sheds light on the variable response to therapeutic cancer vaccines and predicts optimal schedules for vaccination to enhance anti-cancer immunity.

Materials and

Methods: We developed a mechanistic, multiscale compartmental model of cancer patients to simulate the response to cancer vaccination and develop strategies for improving T cell activation in LNs. The multi-scale model includes the arterial system, venous system, lymphatic system, internal organs and skin, and their related LNs to simulate tumor-immune interaction related to T cell trafficking and transport barriers (Fig.1 A, B and C, respectively). In Fig.1 D, we show the effect of antigen level on T cell activation; this process is also sensitive to the fraction of blood flow that enters the LNs. For patients with medium and low antigen production (Fig.1 D), it may be important to consider when and where the vaccination is administered. To assess this, we simulate the temporal distribution of cancer-induced antigen and immunosuppressive agent in different LNs to predict more efficient sites at each time during tumor development for vaccination.

Results, Conclusions, and Discussions: o Results
The model provides a mechanistic framework for optimizing cancer immunotherapy and developing testable solutions to unleash anti-tumor immune responses for more patients with cancer. Our findings highlight that distant lymph nodes (dLNs) exhibit superior potential for activating naïve T (nT) cells. Patients with low tumor antigen production can benefit from tailored antigen vaccination to elevate antigen levels and enhance immune checkpoint inhibition therapy. Simulations underscore the pivotal role of the tumor-draining lymph node (TDLN) in initiating tumor immunity, provided we can mitigate cancer-induced LN-blocking immunosuppressive agents during early cancer development.
Although antigen accumulation in non-TDLNs progresses more slowly, their lower levels of LN-blocking immunosuppressive agent still render them effective sites for nT cell activation. Fig. 2 illustrates simulation results of tumor antigen and immunosuppressive agent distributions in internal organs, skin, and their associated LNs. For example, quickly after tumor initiation, TDLNs accumulate antigen (Fig. 2B) and immunosuppressive agent (Fig. 2B) above threshold levels, while dLNs in organs like the lung, gastrointestinal tract (G.I.), and kidney accumulate immunosuppressive agent before antigen. The remaining dLNs that haven't reached the immunosuppressive agent threshold are effective sites for introducing additional antigen via vaccination.

o Conclusions
1. The model provides a framework for optimizing cancer vaccination and improving anti-tumor immune responses.
2.Key parameters include antigen and immunosuppressive agent production rates and naive T cell trafficking into lymph nodes.
3.Enhancing antigen distribution may improve immunotherapy.
4.Vaccinating far from the tumor site is most efficient.
5.Direct tumor injections are not optimal if suppressive factors are involved.

o Discussion
Our findings indicate that rational targeting of specific lymph nodes, based on spatiotemporal accumulation of antigen and suppressive factors, can significantly improve vaccination efficiency. Generally, lymph nodes far from the tumor or those in small organs, are more favorable for administering antigen cancer vaccines. By simulating the spatiotemporal distributions of tumor-induced antigens and immunosuppressive agent, we can assess the immune response potential in TDLNs and dLNsat different stages of post-tumor formation. These simulations help evaluate the efficacy of different vaccination strategies and guide the scheduling of new vaccinations in distant locations relative to tumor growth.

Acknowledgements (Optional):