The impact of the TIM gene family on tumor immunity and immunosuppression

Abstract

Tumor immunoevasion is an advanced phase of cancer immunosurveillance in which tumor cells acquire the ability to circumvent host immune systems and exploit protumorigenic inflammation. T-cell immunoglobulin mucin (TIM) gene family members have emerged as critical checkpoint proteins that regulate multiple immune response phases and maintain immune homeostasis. Accumulating evidence demonstrates that tumor cells exploit TIM gene family members to evade immunosurveillance, whereas TIM gene family members facilitate the prevention of inflammation-related tumor progression. Thus, a comprehensive analysis to clarify the relative contributions of TIM gene family members in tumor progression may elucidate immunosurveillance systems in cancer patients.

Figure 1

The structure and main domains of TIM gene family members. The sequences (a) and schematic structures (b) are shown for each TIM gene family member. TIM molecules are type-I cell-surface glycoproteins that comprise an extracellular IgV domain, a mucin-like domain, a transmembrane domain and an intracellular cytoplasmic tail. All TIM molecules have a conserved sequence homology in the IgV domains, while other domains show little similarity. The sequence data were generated using the PRALINE multiple sequence alignment function. TIM, T-cell immunoglobulin mucin.

Figure 2

The role of the TIM gene family in antitumor immune responses. TIM molecules regulate multiple immune pathways. (a) TIM-1 expression on T cells regulates the differentiation of T helper subsets,^, whereas TIM-1 expressed on APCs serves as a phagocytosis receptor that facilitates the removal of apoptotic cells. TIM-1 is also expressed on kidney epithelial cells and promotes cell survival through the degradation of nuclear factor NUR77. (b) TIM-2 promotes the differentiation of Th2 cells and regulates T-cell survival and activation upon interaction with Sema4A on myeloid cells.^, (c) TIM-3 on DC suppresses innate immune signals mediated by nucleic acids or DAMPs,^, whereas TIM-3 expressing T cells display exhausted phenotypes and trigger apoptosis by interacting with galectin-9. TIM-3 also regulates NK cell differentiation and function. (d) TIM-4 expression is largely restricted to APCs, and it serves as a phosphatidylserine receptor that regulates the engulfment of apoptotic cells; it interacts with TIM-1 on T cells to regulate the differentiation of Th1 and Th17 cells.^,, APC, antigen-presenting cell; DAMP, damage-associated molecular pattern; DC, dendritic cell; NK, natural killer; Sema4A, Semaphorin 4A; TIM, T-cell immunoglobulin mucin.

Figure 3

The dual role of TIM family members in sterile or inflammatory tumor microenvironments. TIM members may serve as dual regulators of antitumor immune responses depending on the quality of the tumor microenvironment. (a) In sterile, non-inflammatory TMEs, TIM-1 and TIM-4 on APCs suppress antigen-specific immune responses by facilitating tolerogenic phagocytosis. Moreover, TIM-2 may create tolerogenic environments by activating Treg populations, whereas TIM-3 negatively regulates DAMP-mediated innate immune signals and compromises tumor-specific CTL responses. (b) In contrast, immunoregulatory activities mediated by TIM-3 and TIM-4 may have a beneficial role in preventing protumorigenic inflammation, while TIM-1 and TIM-2 have dual roles in tumorigenesis by regulating T helper cell differentiation. DAMP, damage-associated molecular pattern; TIM, T-cell immunoglobulin mucin; Treg, regulatory T cell.