Reshaping the systemic tumor immune environment (STIE) and tumor immune microenvironment (TIME) to enhance immunotherapy efficacy in solid tumors

Abstract

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.

Keywords: Immunotherapy; Radiotherapy; Single-cell transcriptomics; Systemic tumor immune environment (STIE); Tumor immune microenvironment (TIME).

Fig. 1

STIE and TIME relationship. The anatomic and interactive relationship between TIME and STIE as well as key components of STIE are shown. STIE circulating in the blood and lymphatic vessels are in close contact with, and directly provide cell and molecular components to the tumor extracellular matrix which can be considered as part of TIME. The major cell and immune regulator components of STIE and TIME may vary with cancer type, examples of non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), and nasopharyngeal carcinoma (NPC) are summarized in Table 1. CC, cancer cell; CSC, cancer stem cell; Mac, Macrophage; DC, Dendritic cell; MDSC, myeloid-derived suppressor cells; NK, natural killer cells; IDO, Indoleamine 2,3-dioxygenase; Kyn, kynurenine; Trp, tryptophan

Fig. 2

The functions of immune regulator TGF-β1 on TIME and STIE. TGF-β1 has dual roles in the TIME and STIE. TGF-β1 has multiple impacts on different kinds of immune cells. The detail functions of TGF-β1 are shown by different arrows (Solid arrow: stimulation, Dashed arrow: possible stimulation, Vertical-horizontal line: suppression). TGF-β1: Transforming growth factor-beta1; TIME: Tumor Immune Microenvironment; STIE: Systemic Tumor Immune Environment

Fig. 3

The functions of immune regulator IDO on STIE and TIME. Indoleamine 2,3-dioxygenase (IDO) has multiple roles on STIE and TIME. The detailed functions of IDO in different cells as shown by arrows. IDO1, which suppresses Teff cells and MDSC, mainly catalyzes the breakdown of tryptophan (Trp) to kynurenine (Kyn) in the DC: Dendritic cells, Treg, Activated T cells, and APC cells: Antigen-presenting cells. IDO2 catalyzes in B cells. Solid arrow: stimulation, Dashed arrow: possible stimulation; Vertical-horizontal line: suppression. IDO1 and IDO2 are two different enzymes, that catalyze the same reaction. MDSC: Myeloid-derived suppressor cell; Teff: Effector T cells; CAF: Cancer-associated fibroblast; TAM: Tumor-associated macrophage

Fig. 4

STIE and TIME in brain metastasis. The figure shows the modulating role of systemic tumor immune environment (STIE) on the spread of primary tumor to the brain metastasized sites. It is relevant to local therapy such as radiation therapy (RT) and systemic therapy like PD-1 on the left panel and the components of STIE which include all circulating immune modulating molecules such as cytokines like TGF-β1, IDO biomarkers, Artemin and circulating immune cells such as lymphocytes on the right panel

Fig. 5

Therapy induced changes in STIE and TIME. The top panel is a simple schema of “cold” and “hot” tumors, and that PD-1 inhibitor is only effective in “hot” tumor. The 3 lower panels illustrate the transformation of the immune environment from the inactive status to the active status through reshaping STIE and TIME by radiotherapy, chemotherapy, and precision medicine therapy (like targeted therapy). In the left part, PD-1 inhibitor immunotherapy is less effective as the local TIME is cold. In the right part, after receiving various types of therapy, the TIME becomes hot. Meanwhile, more activated immune cells such as CD8⁺ T cells appear in the STIE. PD-1 inhibitor immunotherapy can combine with all these therapies to improve the effectiveness of treatment. Multiple immune cells and immune cell-associated factors are involved in this process [153, 154]. STIE: Systemic Tumor Immune Environment; TIME: Tumor Immune Microenvironment

Fig. 6

Reshape STIE and TIME to prevent metastasis. This figure shows potential reshaping/targeting points to prevent systemic tumor progression, i.e., metastasis, starting from killing/removing tumors in situ in the primary site through radiotherapy/surgery. Upon the cancer metastasis, systemic therapy such as chemotherapy and immunotherapy are the mainstay treatment for these patients. Radiotherapy is frequently needed for either palliation or consolidation local therapy for good responder and palliation for symptoms for patients with disease progression. Single-cell transcriptomics and spatial transcriptomic techniques are useful to detect these therapeutic effects to uncover the underlying mechanism directly in patients. The red and green pipelines are representing blood vessels and lymphatic vessels which establish the connection between Tumor Immune Microenvironment (TIME) and Systemic Tumor Immune Environment (STIE)

Fig. 7

A proposed study schema of STIE and TIME. The pipeline describes a proposed process of studying STIE and TIME including the different treatment strategies and clinical outcomes. The cross-validation of clinical patients and animal models will clearly reveal the STIE and TIME regulation in the RT and PD-1 inhibitor immunotherapy. As the massive data produced by STIE and TIME study, AI model will assist the analysis of data from an in-house or public research