Modelling the tumor immune microenvironment for precision immunotherapy

Abstract

The complexity of the cellular and acellular players within the tumor microenvironment (TME) allows for significant variation in TME constitution and role in anticancer treatment response. Spatial alterations in populations of tumor cells and adjacent non-malignant cells, including endothelial cells, fibroblasts and tissue-infiltrating immune cells, often have a major role in determining disease progression and treatment response in cancer. Many current standard systemic antineoplastic treatments target the cancer cells and could be further refined to directly target commonly dysregulated cell populations of the TME. Recent developments in immuno-oncology and bioengineering have created an attractive potential to model these complexities at the level of the individual patient. These developments, along with the increasing momentum in precision medicine research and application, have catalysed exciting new discoveries in understanding drug-TME interactions, target identification, and improved efficacy of therapies. While rapid progress has been made, there are still many challenges to overcome in the development of accurate in vitro, in vivo and ex vivo models incorporating the cellular interactions that take place in the TME. In this review, we describe how advances in immuno-oncology and patient-derived models, such as patient-derived organoids and explant cultures, have enhanced the landscape of personalised immunotherapy prediction and treatment of solid organ malignancies. We describe and compare different immunological targets and perspectives on two-dimensional and three-dimensional modelling approaches that may be used to better rationalise immunotherapy use, ultimately providing a knowledge base for the integration of the autologous TME into these predictive models.

Keywords: co‐culture; immunotherapy; immuno‐oncology; patient‐derived explants; patient‐derived organoids; precision medicine.

Figure 1

Cellular immunome of the tumor microenvironment. Solid tumors establish both protumoral and immunosuppressive microenvironments comprising complex combinations of various tumor‐derived soluble factors and cytokines to sustain growth, support tumorigenesis and dormancy and promote immune evasion mechanisms. Core to this is the cellular immune components of the tumor microenvironment (TME), including intact, highly activated T‐helper cells, cytotoxic T lymphocytes (CTLs), M1 tumor‐associated macrophages (TAMs) and natural killer (NK) subsets. Following the initiation of oncogenesis, immunological rejection of tumors is largely mediated by tumor‐infiltrating T cells. Chronic activation causes upregulation of exhaustion‐associated molecules, including programmed death‐ligand 1 (PD‐L1), cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and T‐cell immunoglobulin and mucin domain‐containing protein 3 (TIM3). This figure was created with Biorender.com.

Figure 2

Immune checkpoints at the tumor–immune axis displaying checkpoint ligands and clinically relevant inhibitors. Inhibitors with full United States Food and Drug Administration (FDA) approval are indicated in green boxes. BMS, Bristol Meyers Squibb; BSR, British Society for Rheumatology; CD, cluster of differentiation; CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; LAG‐3, lymphocyte activation gene 3; MHC II, human major histocompatibility complex II; OX40, tumor necrosis factor receptor superfamily, member 4; OX40L, OX40 ligand; P2, Phase II clinical trial; P3, Phase III clinical trial; PD‐1, programmed death‐1; PD‐L1, programmed death‐ligand 1; TIGIT, T‐cell immunoreceptor with Ig and ITIM domains; TIM‐3, T‐cell immunoglobulin and mucin domain‐containing 3; VISTA, V‐domain immunoglobulin suppressor of T‐cell activation; VSIG‐3, V‐set and immunoglobulin domain‐containing 3. This figure was created with Biorender.com.

Figure 3

Representation of patient‐derived tumor–immune co‐cultures. A cross section of a microfluidic chamber is displayed, showing primary tumor cells injected into a chamber with whole blood in the adjacent chamber. Pores between these chambers facilitate movement of material across the epithelium. Free floating, or suspended PDOs and PDXs are commonly cultured in an organoid medium with chemo‐ and immunotherapeutic drugs and immune cell activator molecules such as IL‐2. Alternatively, tissue slices or explants may be directly cultured in a basal media such as RPMI alongside chemo‐ and immunotherapeutic drugs to create an air–liquid interface, like what is the case in many organ niches. ALI, air–liquid interface; ICI, immune checkpoint inhibitor; IL‐2, interleukin‐2; PBMCs, peripheral blood mononuclear cells; and PDO, patient‐derived organoid. This figure was created with Biorender.com.

Figure 4

Summarised workflow for immunological analysis of patient material in cancer. Tumor tissue is processed into PDOs, PDXs or slices, and whole peripheral blood is harvested for PBMC extraction. These autologous components are then cultured together, commonly in suspension, at the air–liquid interface or processed into a microfluidic chip. Addition of anticancer drugs followed by systemic functional and quantitative analysis allows for the identification and prevalence of clinically relevant immune checkpoints and a predictive examination of the efficacy of treatment. ACT, adoptive cell transfer; CAR‐T, chimeric antigen receptor T cell. This figure was created with Biorender.com.