Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

When the immune system responds to tumour development, patterns of immune infiltrates emerge, highlighted by the expression of immune checkpoint-related molecules such as PDL1 on the surface of cancer cells. Such spatial heterogeneity carries information on intrinsic characteristics of the tumour lesion for individual patients, and thus is a potential source for biomarkers for anti-tumour therapeutics. We developed a systems biology multiscale agent-based model to capture the interactions between immune cells and cancer cells, and analysed the emergent global behaviour during tumour development and immunotherapy. Using this model, we are able to reproduce temporal dynamics of cytotoxic T cells and cancer cells during tumour progression, as well as three-dimensional spatial distributions of these cells. By varying the characteristics of the neoantigen profile of individual patients, such as mutational burden and antigen strength, a spectrum of pretreatment spatial patterns of PDL1 expression is generated in our simulations, resembling immuno-architectures obtained via immunohistochemistry from patient biopsies. By correlating these spatial characteristics with in silico treatment results using immune checkpoint inhibitors, the model provides a framework for use to predict treatment/biomarker combinations in different cancer types based on cancer-specific experimental data.

Quantitative systems pharmacology (QSP) models and spatial agent-based models (ABM) are powerful and efficient approaches for the analysis of biological systems and for clinical applications. Although QSP models are becoming essential in discovering predictive biomarkers and developing combination therapies through in silico virtual trials, they are inadequate to capture the spatial heterogeneity and randomness that characterize complex biological systems, and specifically the tumor microenvironment. Here, we extend our recently developed spatial QSP (spQSP) model to analyze tumor growth dynamics and its response to immunotherapy at different spatio-temporal scales. In the model, the tumor spatial dynamics is governed by the ABM, coupled to the QSP model, which includes the following compartments: central (blood system), tumor, tumor-draining lymph node, and peripheral (the rest of the organs and tissues). A dynamic recruitment of T cells and myeloid-derived suppressor cells (MDSC) from the QSP central compartment has been implemented as a function of the spatial distribution of cancer cells. The proposed QSP-ABM coupling methodology enables the spQSP model to perform as a coarse-grained model at the whole-tumor scale and as an agent-based model at the regions of interest (ROIs) scale. Thus, we exploit the spQSP model potential to characterize tumor growth, identify T cell hotspots, and perform qualitative and quantitative descriptions of cell density profiles at the invasive front of the tumor. Additionally, we analyze the effects of immunotherapy at both whole-tumor and ROI scales under different tumor growth and immune response conditions. A digital pathology computational analysis of triple-negative breast cancer specimens is used as a guide for modeling the immuno-architecture of the invasive front.

Quantitative systems pharmacology (QSP) models have become increasingly common in fundamental mechanistic studies and drug discovery in both academic and industrial environments. With imaging techniques widely adopted and other spatial quantification of tumor such as spatial transcriptomics gaining traction, it is crucial that these data reflecting tumor spatial heterogeneity be utilized to inform the QSP models to enhance their predictive power. We developed a hybrid computational model platform, spQSP-IO, to extend QSP models of immuno-oncology with spatially resolved agent-based models (ABM), combining their powers to track whole patient-scale dynamics and recapitulate the emergent spatial heterogeneity in the tumor. Using a model of non-small-cell lung cancer developed based on this platform, we studied the role of the tumor microenvironment and cancer–immune cell interactions in tumor development and applied anti-PD-1 treatment to virtual patients and studied how the spatial distribution of cells changes during tumor growth in response to the immune checkpoint inhibition treatment. Using parameter sensitivity analysis and biomarker analysis, we are able to identify mechanisms and pretreatment measurements correlated with treatment efficacy. By incorporating spatial data that highlight both heterogeneity in tumors and variability among individual patients, spQSP-IO models can extend the QSP framework and further advance virtual clinical trials.

Quantitative characterization of the tumor microenvironment, including its immuno-architecture, is important for developing quantitative diagnostic and predictive biomarkers, matching patients to the most appropriate treatments for precision medicine, and for providing quantitative data for building systems biology computational models able to predict tumor dynamics in the context of immune checkpoint blockade therapies. The intra- and inter-tumoral spatial heterogeneities are potentially key to the understanding of the dose-response relationships, but they also bring challenges to properly parameterizing and validating such models. In this study, we developed a workflow to detect CD8+ T cells from whole slide imaging data, and quantify the spatial heterogeneity using multiple metrics by applying spatial point pattern analysis and morphometric analysis. The results indicate a higher intra-tumoral heterogeneity compared with the heterogeneity across patients. By comparing the baseline metrics with PD-1 blockade treatment outcome, our results indicate that the number of high-density T cell clusters of both circular and elongated shapes are higher in patients who responded to the treatment. This methodology can be applied to quantitatively characterize the tumor microenvironment, including immuno-architecture, and its heterogeneity for different cancer types.

Response to cancer immunotherapies depends on the complex and dynamic interactions between T cell recognition and killing of cancer cells that are counteracted through immunosuppressive pathways in the tumor microenvironment. Therefore, while measurements such as tumor mutational burden provide biomarkers to select patients for immunotherapy, they neither universally predict patient response nor implicate the mechanisms that underlie immunotherapy resistance. Recent advances in single-cell RNA sequencing technology measure cellular heterogeneity within cells of an individual tumor but have yet to realize the promise of predictive oncology. In addition to data, mechanistic multiscale computational models are developed to predict treatment response. Incorporating single-cell data from tumors to parameterize these computational models provides deeper insights into prediction of clinical outcome in individual patients. Here, we integrate whole-exome sequencing and scRNA-seq data from Triple-Negative Breast Cancer patients to model neoantigen burden in tumor cells as input to a spatial Quantitative System Pharmacology model. The model comprises a four-compartmental Quantitative System Pharmacology sub-model to represent a whole patient and a spatial agent-based sub-model to represent tumor volumes at the cellular scale. We use the high-throughput single-cell data to model the role of antigen burden and heterogeneity relative to the tumor microenvironment composition on predicted immunotherapy response. We demonstrate how this integrated modeling and single-cell analysis framework can be used to relate neoantigen heterogeneity to immunotherapy treatment outcomes. Our results demonstrate feasibility of merging single-cell data to initialize cell states in multiscale computational models such as the spQSP for personalized prediction of clinical outcomes to immunotherapy.