Heterogeneity of the tumor immune microenvironment and its clinical relevance

Abstract

During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies.

Keywords: Heterogeneity; Immune checkpoint blockade; Immunotherapy; Tumor microenvironment.

Fig. 1

Origin and pattern of tumor immunological heterogeneity. Spatial heterogeneity represents an uneven localized immunological component within single tumor, or among intra-individually metastasized tumors. Temporal heterogeneity denotes the evolutionary dynamics of immunological components along the course of tumor progression, or in response to clinical intervention. Tumor immunological heterogeneity was originated from tumoral intrinsic event including genomic instability and epigenetic modification, or originated from extrinsic events such as environmental perturbations or therapeutic pressure

Fig. 2

Spatial heterogeneity of immune microenvironment. Tumor immune microenvironment was reported that can be broadly divided into immune-hot or -cold based on whether it favor an effective anti-tumor immune response or not. Representative traits of a heterogeneous immune microenvironment including the spectrum of neoantigen, the infiltration of immunological suppressive cells and effector cells, the status of vasculature, the milieu of cytokine/nutrient and metabolic program

Fig. 3

Strategies to overcome immunological heterogeneity-related resistance to therapies. Selective outgrowth of resistant clones to traditional therapeutic paradigms. Survived clones from initial anti-tumor treatment contribute to drug resistance. Alternatively, boosting immunogenic microenvironment with novel therapies contribute to overcome drug resistance