An optimal control approach for enhancing natural killer cells' secretion of cytolytic molecules

Abstract

Natural killer (NK) cells are immune effector cells that can detect and lyse cancer cells. However, NK cell exhaustion, a phenotype characterized by reduced secretion of cytolytic models upon serial stimulation, limits the NK cell's ability to lyse cells. In this work, we investigated in silico strategies that counteract the NK cell's reduced secretion of cytolytic molecules. To accomplish this goal, we constructed a mathematical model that describes the dynamics of the cytolytic molecules granzyme B (GZMB) and perforin-1 (PRF1) and calibrated the model predictions to published experimental data using a Bayesian parameter estimation approach. We applied an information-theoretic approach to perform a global sensitivity analysis, from which we found that the suppression of phosphatase activity maximizes the secretion of GZMB and PRF1. However, simply reducing the phosphatase activity is shown to deplete the cell's intracellular pools of GZMB and PRF1. Thus, we added a synthetic Notch (synNotch) signaling circuit to our baseline model as a method for controlling the secretion of GZMB and PRF1 by inhibiting phosphatase activity and increasing production of GZMB and PRF1. We found that the optimal synNotch system depends on the frequency of NK cell stimulation. For only a few rounds of stimulation, the model predicts that inhibition of phosphatase activity leads to more secreted GZMB and PRF1; however, for many rounds of stimulation, the model reveals that increasing production of the cytolytic molecules is the optimal strategy. In total, we developed a mathematical framework that provides actionable insight into engineering robust NK cells for clinical applications.

Phosphatases are predicted to govern prolactin-mediated JAK-STAT signaling in pancreatic beta cells

“…We implement Bayesian parameter estimation using the Metropolis-Hastings algorithm, and most of our protocol mirrors the approach used in previous work [16,17]. Supplementary Table 1 includes all parameters used to define the distribution of the likelihood, prior, and proposal.…”

Next‐generation chimeric antigen receptors for T‐ and natural killer‐cell therapies against cancer

“…176 The SynNotch system has also been used to increase the secretion of granzyme B (GZMB) and perforin (PRF1) by NK cells and to regulate their intracellular pools by coupling them with pSHP inhibition. 177 Similarly, NK cells engineered to express a logic-gated GPC3-SynNotch-inducible CD147-CAR were shown to have increased specificity against hepatocellular carcinoma and reduced toxicity in preclinical models, as both antigens were required for the full-targeted activity of these CAR NK cells. 178 However, the immunogenicity potential of the SynNotch receptor, a nonhuman artificial protein, as well as the high level of background signaling due to ligand-independent receptor activity pose safety concerns.…”

Tumor-immune ecosystem dynamics define an individual Radiation Immune Score to predict pan-cancer radiocurability

“…Simulating the highly dynamic tumor responses to radiation based on individual patient properties holds promise for innovative translational opportunities [14] , [15] , [16] , [17] , 18 , [19] , [20] . Similarly, significant inroads have been made in mathematical modeling of tumor-immune interactions and immunotherapy response prediction [21] , [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , as well as understanding the local and systemic mechanistic consequences of radio-immunotherapy combinations [31] , [32] , [33] , [34] .…”