The war between the immune system and the tumor - using immune biomarkers as tracers

Abstract

Nowadays, immunotherapy is one of the most promising anti-tumor therapeutic strategy. Specifically, immune-related targets can be used to predict the efficacy and side effects of immunotherapy and monitor the tumor immune response. In the past few decades, increasing numbers of novel immune biomarkers have been found to participate in certain links of the tumor immunity to contribute to the formation of immunosuppression and have entered clinical trials. Here, we systematically reviewed the oncogenesis and progression of cancer in the view of anti-tumor immunity, particularly in terms of tumor antigen expression (related to tumor immunogenicity) and tumor innate immunity to complement the cancer-immune cycle. From the perspective of integrated management of chronic cancer, we also appraised emerging factors affecting tumor immunity (including metabolic, microbial, and exercise-related markers). We finally summarized the clinical studies and applications based on immune biomarkers. Overall, immune biomarkers participate in promoting the development of more precise and individualized immunotherapy by predicting, monitoring, and regulating tumor immune response. Therefore, targeting immune biomarkers may lead to the development of innovative clinical applications.

Keywords: Cancer; Immune biomarker; Immunotherapy; Tumor immunity.

Fig. 1

Various links in the development of tumor immunity. Initiation of the tumor immune response: A induce tumor cell ICD to release tumor antigens or promote tumor cell surface expression of pMHC to enhance immunogenicity. Building the first line of defense against tumors: B antitumor innate immune responses, including NK cells and macrophages, kill tumor cells through a balance of inhibitory and activating signals. Activated the second line of anti-tumor defense: C DC captured tumor antigens and migrated to TDLN and gradually matured. D DCs present antigen to T cells. The march of immune cells into the tumor stronghold: E chemokine-regulated immune recruitment in the peripheral blood circulation. F permeable malformed tumor neovascularization. G penetrate the tumor ECM with a rigid structure and immunosuppressive properties. Immune cells form the provisional command of the front line: H the formation of TLS. T cells exert effect: I T cells kill tumor cells through a balance of three signals

Fig. 2

Balance between inhibitory and activation of cell-surface immune checkpoints. Anti-tumor innate immunity: NK cells regulate their activation state mainly through the balance of a series of activating killer cell receptors (AKRs, mainly recognizing non-MHCI molecules) and inhibitory killer cell receptors (IKRs, mainly recognizing MHCI molecules). Macrophages regulate their activation state mainly through the balance of a series of ‘eat me’ (DAMPs) and ‘don’t eat me’ (SIRPa) signals. Anti-tumor adaptive immunity: T cells regulate their activation state mainly through the balance of a series of TCR-pMHC, costimulatory molecules and cytokine signaling

Fig. 3

Important off-field factors affecting tumor immunity. In addition to tumor immunity itself, metabolic reprogramming (especially lipid metabolism) of tumor and related immune cells, as well as specific trace elements and vitamins affect the energy competition between cells at the metabolic level. As a new field of tumor immunity, tumor microbes and the microenvironment they create affect various aspects of tumor immunity, such as tumor immunogenicity, antigen presentation, ICD, metabolism, and ICs. In addition, exercise and bad habits also play an auxiliary role in tumor immune response that cannot be ignored. The above factors can be used as potential targets for regulating TME and improving immunotherapy

Fig. 4

Tumor antigen-based treatment strategies. Tumor antigen-based therapies encompass tumor vaccines, ACT, tumor antibodies, and inducers of ICD. Tumor vaccines emulate the mechanism through which tumor cells release or express tumor antigens, thereby initiating and augmenting anti-tumor T cell immune responses. These vaccines offer many advantages, including eliciting a broad spectrum of anti-tumor immunity, exhibiting high variability, and demonstrating robust efficacy in overcoming tumor heterogeneity. Compared to established vaccines for infectious diseases, tumor vaccines are relatively straightforward and cost-effective to prepare, except for DC vaccines. However, their utilization in clinical settings remains infrequent. Adoptive cell therapy replicates the procedure of screening and amplifying anti-tumor immune cells, resulting in a substantial enhancement in both quantity and efficacy of these cells. The advantages of ACT in anti-tumor immunity encompass robust and enduring response, prompt initiation, heightened specificity, and potent capacity to overcome immunosuppression. Thereby, ACT circumvents the issue of adverse effects associated with excessive immune stimulation. Nevertheless, certain challenges persist, including limited scope of anti-tumor immune response, diminished variability, inadequate ability to surmount tumor heterogeneity, arduous preparation, protracted process and high cost. Synthetic tumor-targeting antibodies emulate the functional mechanism of naturally occurring antibodies in vivo, thus labeling tumor cells, promoting ADCC effect, blocking tumor-promoting receptor signaling, connecting target cells with killer cells, and carrying anti-tumor substances. Tumor antibodies have the advantages of strong anti-tumor immune responses, high specificity, low side effects and relatively simple preparation, especially for hematological tumors. They account for a large part of the researches and development of anticancer drugs and some of them have entered clinical application. ICD inducers promote tumor production of DAMPs to activate anti-tumor innate and adaptive immune responses. The current clinical application of ICD inducers tends to combine them with immunotherapy or targeted drugs for anti-tumor therapy, and to develop new drug delivery methods

Fig. 5

Immune checkpoint-based treatment strategies. Tumor cells actively interact with the surrounding TME and develop various adaptive strategies to form a continuously progressive and highly heterogeneous whole. Various ICs regulate tumor immune responses through a balance of inhibitory and activating signals. In addition to classical cell-surface ICs (such as PD-1/PD-L1 and CTLA-4), they also include extracellular ICs (such as TNF-α and TGF-β), intracellular ICs (such as NF-κB, STING, NR2F6 and LMTK3) and metabolism-related ICs (such as IDO and CD73). More and more ICs pathways have been found to play an important role in driving tumor immune escape. Therefore, ICS pathway may become a promising target for the development of new anticancer immunotherapy