Dynamics and Plasticity of Immune Cells within Tumor Microenvironment

Extensive research has been conducted on the heterogenicity of immune cells within the tumor microenvironment, like cancer cell heterogenicity, particularly with the emergence of single cell analysis. While inducing factors have been used to artificially alter immune cell fate in vitro and dynamic cancer cell plasticity has been recently discovered, it remains unknown whether tumor infiltrating immune cells acquire plasticity and dynamics that contribute to heterogenicity. In this study, we explored mitochondrial DNA mutation combining with chromosome single nucleotide polymorphism to construct phylogenetic trees of immune cells within multiple solid tumors, together with precise cell type and subtype definition based on single cell RNA sequencing data. Based on these lineage tracing landscapes, we systematically identified cell state transitions and fate changes among different immune cell subtypes and types within multiple solid tumors. Interestingly, immune cells demonstrated a high level of plasticity for transitioning between different states, transdifferentiating from one type to another or dedifferentiating to a progenitor stage, in varying frequencies across different cancers. Moreover, most of these cell state transitions and cell fate changes discovered here were previously unknown. The cell changes may arise from extrinsic growth factors and cytokines secreted by tumor microenvironment cells, but intrinsic genetic mutations, particularly those related to ribosomes, may also be involved. Our data reveal that immune cell complexity extends beyond heterogenicity and also encompasses plasticity similar to that of cancer cells. Understanding the underlying mechanism of these cell changes will help elucidate the role of immune cells in cancer development and manipulating the cell change direction may ultimately enhance the efficiency of current immunotherapy.