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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.

SUBMITTER: Xu L

PROVIDER: S-EPMC9264569 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Xu Liangliang L Zou Chang C Zhang Shanshan S Chu Timothy Shun Man TSM Zhang Yan Y Chen Weiwei W Zhao Caining C Yang Li L Xu Zhiyuan Z Dong Shaowei S Yu Hao H Li Bo B Guan Xinyuan X Hou Yuzhu Y Kong Feng-Ming FM

Journal of hematology & oncology 20220707 1

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 ...[more]

PMID: 35799264

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Project description:IntroductionDespite recent advances, triple-negative breast cancer (TNBC) patients remain at high risk for recurrence and metastasis, which creates the need for innovative therapeutic approaches to improve patient outcomes. Cryoablation is a promising, less invasive alternative to surgical resection, capable of inducing tumor necrosis via freeze/thaw cycles. Necrotic cell death results in increased inflammatory signals and release of preserved tumor antigens, which have the potential to boost the local and systemic anti-tumor immune response. Thus, compared to surgery, cryoablation enhances the activation of T cells leading to an improved abscopal effect, defined as the occurrence of a systemic response after local treatment. We previously showed with a bilateral-tumor mouse model of TNBC that cryoablation of the primary tumor leads to increased infiltration of distant (abscopal) tumors by tumor infiltrating lymphocytes (TILs) and decreased rates of recurrence and metastasis. However, the early drivers of the cryoablation generated abscopal effect are still unknown and knowledge of the mechanism could provide insight into improving the anti-tumor immune response through pharmacologic immune modulation in addition to cryoablation.MethodsOne million 4T1-12B-luciferase expressing cells were transplanted into the mammary fat pad of BALB/c mice. Two weeks later, left (primary) tumors were either resected or cryoablated. A week after the procedure, right (abscopal) and left tumors, along with spleen, tumor-draining lymph node and blood were collected and processed for flow cytometry and/or RNA-sequencing and immunofluorescence.ResultsHere we show that cryoablation of mouse mammary carcinomas results in smaller abscopal tumors that harbor increased frequencies of anti-tumor cells [such as natural killer (NK) cells], accompanied by a systemic increase in the frequency of migratory conventional type 1 dendritic cells (cDC1; CD103+ XCR1+), compared to resection. The changes in cell frequencies are mirrored by the immune gene signature of the abscopal tumors, with cryoablation inducing genes involved with NK cell activation and leukocyte-mediated toxicity, including IL11ra1 and Pfr1.ConclusionsThese results better define the early mechanisms through which cryoablation improves tumor elimination, which is mediated by enhanced frequencies of anti-tumoral cells such as NK and cDC1s at the abscopal tumor and in the spleen of mice treated with cryoablation, respectively.

Project description:Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.

Dataset Information

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

Publications

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

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