Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine

Abstract

Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.

Keywords: cancer Immunobiology; cancer epidemiology; cancer prevention; colorectal carcinoma; molecular pathology.

Figure 1

Various exogenous and endogenous factors (collectively called ‘exposures’) influence a tumour that has intrinsic and interacting components of neoplastic cells and the immune system. For simplicity, this does not depict complex interactions between the exposures and between neoplastic cells. There are ample research opportunities to decipher the interactions between these factors and components in human subjects and populations for better understanding of neoplasms. This figure illustrates potentials of integration of immunology and molecular pathological epidemiology.

Figure 2

Hypothesis testing in molecular pathological epidemiology (MPE) in a study of immune subtypes of disease A, with the simplest binary subtyping (subtypes B and C). Note that disease subtyping systems are often more complicated than simple dichotomy. Hypothesis testing #1 or #2 is on the relationship between an exposure of interest and each subtype. In this illustration, the exposure is hypothesised to prevent subtype B. Hypothesis testing #3 is unique to MPE, and concerns on a difference (heterogeneity) between the relationships of the exposure with the immune subtypes B and C.

Figure 3

Overview of research designs to integrate immunity analyses into the framework of molecular pathological epidemiology. The word ‘exposures’ is broadly used as an epidemiological term for variables that can causally influence disease incidence, status or outcome. Immunity assessments include germline genotyping of immune-related genes, analyses of immunity status in disease tissue and analyses of biomarkers on tissue, blood and/or other body fluids as intermediary phenotypes. Intermediary phenotypes refer to phenotypes that are thought to precede full-blown disease phenotypes or subsequent clinical outcome (eg, mortality), and can be typically assessed in radiological images, biopsy tissue, peripheral blood or other body fluids. Intermediary phenotype variables can be used as exposures or outcomes in epidemiological terms.

Figure 4

Illustration of the molecular pathological epidemiology approach using tumour immunity status. The germline DNA polymorphism rs11676348 is a risk allele for IBD. Because IBD is a risk factor for colorectal cancer, the rs11676348 polymorphism is considered to be a risk factor for colorectal cancer. The Genetics and Epidemiology of Colorectal Cancer Consortium study showed the OR estimate of 1.08 per rs11676348 risk allele, indicating a very weak association with overall colorectal cancer. When colorectal cancer was classified by immune response features, the association of the risk allele was stronger (OR estimate of 1.47 per risk allele) and specific for colorectal cancer subtype with Crohn’s-like lymphoid reaction, but not for subtype without Crohn’s-like lymphoid reaction.

Figure 5

Roadmap of integrative immunology-molecular pathological epidemiology (MPE) to precision medicine. Three themes are set to start integrated immunology-MPE research and accomplish three specific aims. Based on data from research for the three specific aims, strategies 1 through 3 will help us implement, monitor and optimise tumour immunity testing for clinical use.