Spatial Immune Cell Heterogeneity in the Tumor Microenvironment

Cancer cells have been shown to be capable of escaping immune surveillance and antitumor immune mechanisms deployed by both innate and adaptive immune cells. These mechanisms have been deciphered to an extent by long standing research on tumor microenvironment and immune checkpoints leading to the development of immune checkpoint inhibitors (ICIs). The ICIs have indeed been novel therapeutic targets to generate robust anti-tumor immune response and have emerged as a prominent form of immunotherapy. Yet, the benefit of ICIs have been demonstrated only in a small subgroup of patients in the clinical trials. In solid tumors, one of the major reasons for not obtaining optimal response from the ICIs has been attributed to the tumor microenvironmental spatial heterogeneity, due to the remodeling of the intrinsic tissue architecture that dramatically affects the distribution of the tumor infiltrating immune cells.

The tumor immune microenvironment has been experimentally shown to exert a significant role in predicting response to immunotherapy. The complex multidimensional interaction between tumor cells, immune cells (especially tumor infiltrating leukocytes, i.e TILs) and their longitudinal temporal evolution is shown to orchestrate spatial intratumor heterogeneity. Selection pressure exerted in the tumor microenvironment via hypoxia, tissue stiffness, immune infiltration and differential vascular supply strongly influence cancer development and progression and reciprocally allows the cancer cells to modify their own environment leading to highly variable response to treatment modalities. This spatial heterogeneity leads to variable degrees of cancer immune escape phenomenon resulting in partial or no response to ICIs. Hence analysis of the tumor immune microenvironment provides a very promising source to develop immunotherapy biomarkers. Quantitative measurement of immune heterogeneity bears the challenge of developing methods preserving the architectural integrity of the samples. Multiplexed quantitative immunofluorescence to study the TIL subsets, multispectral immunohistochemistry (IHC) and tissue microarray (TMA) to study the tumor composition, methods for classifying tumors based on immune cell infiltration such as Immunoscore and spatially variant immune infiltration scoring such as SpatialVizScore are some of the techniques that are being utilized for better understanding tumor spatial immune cell distribution.

This special issue is focused on expanding the current knowledge on the role of spatial immune cell heterogeneity in tumor microenvironment in predicting response to cancer immunotherapy. We welcome the submission of Original Research, Review, Mini Review, Clinical Trial, covering, but not limited to, the following sub-topics:
• Factors and druggable targets including novel immune checkpoints in determining spatial immune cell heterogeneity and therapeutic strategies in inhibiting such factors and targets.
• Cutting edge methods to quantitively measure immune cell heterogeneity in cancer cells
• Differential expression of immune cells as prognostic factors in tumors and in predicting disease outcome to ICI treatments.
• Scoring methods to predict spatial immune heterogeneity using different IHCs and statistical tools.
• Studies investigating spatial heterogeneity in terms of clonal composition of tumor cells and characterization of other TME cells using emerging biomedical technologies and spatial transcriptomic data.

Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation are considered out of scope of this section.

Topic editor Dr. Sumit Mukherjee is employed by Actinium Pharmaceuticals. All other Topic Editors declare no competing interests with regards to the Research Topic subject.