The molecular mechanism of actions and clinical utilities of tumor infiltrating lymphocytes in gastrointestinal cancers: a comprehensive review and future prospects toward personalized medicine

Abstract

Gastrointestinal (GI) cancers remain a significant global health burden, accounting for a substantial number of cases and deaths. Regrettably, the inadequacy of dependable biomarkers hinders the precise forecasting of patient prognosis and the selection of appropriate therapeutic sequencing for individuals with GI cancers, leading to suboptimal outcomes for numerous patients. The intricate interplay between tumor-infiltrating lymphocytes (TILs) and the tumor immune microenvironment (TIME) has been shown to be a pivotal determinant of response to anti-cancer therapy and consequential clinical outcomes across a multitude of cancer types. Therefore, the assessment of TILs has garnered global interest as a promising prognostic biomarker in oncology, with the potential to improve clinical decision-making substantially. Moreover, recent discoveries in immunotherapy have progressively changed the landscape of cancer treatment and significantly prolonged the survival of patients with advanced cancers. Nonetheless, the response rate remains constrained within solid tumor sufferers, even when TIL landscapes appear comparable, which calls for the development of our understanding of cellular and molecular cross-talk between TIME and tumor. Hence, this comprehensive review encapsulates the extant literature elucidating the TILs' underlying molecular pathogenesis, prognostic significance, and their relevance in the realm of immunotherapy for patients afflicted by GI tract cancers. Within this review, we demonstrate that the type, density, and spatial distribution of distinct TIL subpopulations carries pivotal implications for the prediction of anti-cancer treatment responses and patient survival. Furthermore, this review underscores the indispensable role of TILs in modulating therapeutic responses within distinct molecular subtypes, such as those characterized by microsatellite stability or programmed cell death ligand-1 expression in GI tract cancers. The review concludes by outlining future directions in TIL-based personalized medicine, including integrating TIL-based approaches into existing treatment regimens and developing novel therapeutic strategies that exploit the unique properties of TILs and their potential as a promising avenue for personalized cancer treatment.

Keywords: gastrointestinal tract cancer; immune infiltration; immune microenvironment; immunotherapy; tumor-infiltrating lymphocytes.

Figure 1

Orchestra of the Tumor microenvironment (TME): The tumor microenvironment is the environment surrounding a tumor inside the body. It includes immune cells, the extracellular matrix, blood vessels, and other cells, like fibroblasts; different TME cells and components are mentioned in the figure (Created with BioRender.com).

Figure 2

(A) Early stage of cancer development: Cytotoxic T lymphocytes (CTL), which are differentiated from CD8⁺ T-cells via IL-2, are able to destroy tumor cells by releasing perforin and granzymes. IL-2 plus IFN-γ is released by CD4⁺ cells after activation through MHC presented by APC cells. IFN-γ increases the expression of represented MHC by APCs to CD8⁺ T-cells and also enhances the differentiation of CD4⁺ cells into T helper-1(Th1). (B)Immune evasion mechanisms: 1) Genomic instability, immune evasion, angiogenesis, and metastatic dissemination are among the elements that lead to tumor progression. One factor that leads to the stimulation of cases is said to be chronic inflammation, which plays a vital role in the development of cancer. 2) various factors, including Tregs, suppress or activate effector immune cells. Inhibiting the immune system using suppressive molecules or different surface receptors, inhibiting the function of dendritic cells (DC), and releasing inflammatory cytokines are among the parts of Treg in this system. Also, inhibition of Teff activation in 2 ways by limiting TCR ligand binding and using granzyme and metabolic disorders are other functions of Tregs. 3) Furthermore, CTLs fail to recognize tumor cells, and this is due to the reduction of MHC-I presented by APCs to CD8⁺ T-cells. 4) Tumor cells use FAS ligand (FasL) proteins to suppress CTLs, leading to their apoptosis, and finally induce inhibition of immune response (Created with BioRender.com).

Figure 3

Immune cell differentiation in tissue. (A) Tumor cells are killed by two mechanisms when confronting cytotoxic T lymphocytes (CTL) activated by antigen-presenting cells (APC): first, cytolysis by releasing perforin and granzyme from CTLs. Second, the expression of death ligands FasL and TNF-related apoptosis-inducing ligands (TRAIL) on the surface of CTLs, whose interaction with the relevant death receptors leads to cancer cell apoptosis. (B) After penetrating the tissue and being activated by APCs, Naive CD4+ T cells differentiate into three different forms and have different functions: 1) Th1, secretion of IFN-g, TNF-a, and IL-2 to increase the toxicity and antitumor activity of CTLs, macrophages, and NK cells. 2) Th 2, by secreting different cytokines, promotes tumor cells to develop cancer. 3) Treg suppresses the cytotoxic activity of CTLs by using suppressor molecules. (C) After the penetration of naive B cells into the tissue, they are distinguished in three ways with specific functions: 1) Tumor-infiltrating B cells cause Th1 polarization and toxicity of cells by secreting IFN-γ and IL-12. 2) Plasma cells secrete tumor-specific antibodies and cause phagocytosis of tumor cells and stimulation of complement cascade. 3) Bregs, secretion of immune regulatory cytokines to Th2 polarization and inhibit the activity of CTLs (Created with BioRender.com).

Figure 4

Mechanism of inhibition of PD1/PDL1 axis by tumor cells: After activation of CD 8⁺ T-Cell by MHC-I, IFN is secreted and activates the transcription factor IRF in the nucleus and, finally, the expression of PDL 1 in tumor cells. On the other hand, TCR signaling leads to an increase in the PD1 expression on the surface of T cells and the activation of the PD 1/PDL 1 axis, and the interactions between these two ultimately reduce the antitumor effects of T cells. Anti-PD1/PDL1 antibodies, as an effective treatment method, block the PD1/PDL1 function and increase immune cells’ antitumor activity (Created with BioRender.com).

Figure 5

MSI status leads to a potent immune response. Neoantigens are produced by tumor cells due to genomic mutations, such as mutations in the DNA mismatch repair system (MMR) that lead to microsatellite instability (MSI). These antigens interact with T cell receptors (TCR) to increase the production of TILs. TILs recognize these antigens and induce a robust immune response (Created with BioRender.com).

Figure 6

Schematic Illustration of the Immunoscore (IS) determination. In the top left image, digital pathology software is used to automatically identify tumor (CT) tissue, invasive margin (IM), and normal tissue in colon cancer samples. In the top right images, the software also automatically detects the numbers of CD3⁺ and CD8⁺ T-cells. The bottom chart illustrates the calculation of the IS for colon cancer. The method involves converting the densities of CD3⁺ and CD8⁺ T-cells in both the CT and IM into percentile values. Then, the means of four percentiles are calculated for the IS. In a three-category IS analysis, the mean densities within the ranges of 0-25%, 25-70%, and 70-100% are categorized as “low,” “intermediate,” and “high,” respectively. In a two-category analysis, the mean densities between 0-25% are labeled as “low,” while densities ranging from 25-100% are classified as “intermediate-high.”