Novel strategies for cancer immunotherapy: counter-immunoediting therapy

Abstract

The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.

Fig. 1

The three phases of cancer immunoediting: elimination, equilibrium, and escape. a During the elimination phase, the innate and adaptive immune systems synergize to identify and eliminate malignant or transformed tumor cells before clinical detection. b During the equilibrium phase, a relative balance is established between the tumor cells and the immune system, with the immune system unable to completely eliminate the tumor cells and the tumor cells unable to evade immune surveillance. c During the escape phase, tumor cell growth and proliferation are no longer restricted by the immune system. The accumulation of rapidly proliferating tumor cells in combination with other stromal cells creates a more complex immunosuppressive microenvironment, thus further damaging the balance between tumor cells and the immune system. During the proceeding of cancer immunoediting, the ability of the immune system to monitor, recognize, and kill tumor cells is crucial in halting its progression. Factors that enhance this ability are positive, while those that enable tumor cells to evade immune recognition and killing are negative. The impact of these factors in the process of cancer immunoediting has been quantified and classified as strong expression (score 4), moderate intensity expression (score 3), weak expression (score 2), and pianissimo expression (score 1). TAMs, tumor-associated macrophages; MDSCs, nyeloid-derived suppressor cells; MHC, major histocompatibility complex; GzmB: Granzyme B

Fig. 2

Four immunophenotypes of tumor microenvironment based on the driving factors. a Oncogene-driven type, b Stromal cell-driven type, c Immunsuppressive cell-driven type, and d Exhausted T cell-driven type. e We summarized the characteristics of each tumor type and ranked the importance of these characteristics in the different types. TAMs Tumor-associated macrophages, CAFs Tumor-associated fibroblasts, MDSCs Myeloid-derived suppressor cells, MSCs Mesenchymal Stem Cell, ECM Extracellular matrix, MHC Major histocompatibility complex

Fig. 3

Pattern diagram of normalized treatment strategies targeting four tumor immunophenotypes. a Normalization of stromal cells, a therapeutic strategy to counter the proceeding of cancer immunoediting by targeting multiple stromal cells in the TME. b Normalization of immunity, a therapeutic strategy to counter the proceeding of cancer immunoediting by targeting multiple immunosuppressive factors in the TME. c Normalization of tumor cells, a therapeutic strategy to counter the proceeding of cancer immunoediting by targeting tumor cells and related factors in the TME. TAMs Tumor-associated macrophages, CAFs Tumor-associated fibroblasts, MDSCs Myeloid-derived suppressor cells, MSCs Mesenchymal Stem Cell, ECM Extracellular matrix, MHC Major histocompatibility complex, DCs Dendritic cells, RTKs Receptor tyrosine kinase inhibitors, OA Oncolytic adenovirus

Fig. 4

Model of microscopic changes in the TME after normalization therapy. a–f illustrate a series of changes in the TME resulting from the combined application strategies of normalization therapy. a represents the untreated TME; b represents the TME that has been remodeled after receiving normalization therapy of stromal cells; c represents the TME that becomes immunosuppressive due to the stimulation of continuous pro-inflammatory factors; d represents the TME that has undergone normalization therapy of immunity; e represents the TME formed by tumor cell-mediated immune escape in the presence of continuous inflammatory factors; f represents the tumor regression after normalization therapy of tumor cells; g depicts the dynamic changes of immune cells within the vasculature of the untreated TME; h depicts the dynamic changes of immune cells within the vasculature after receiving normalization therapy of stromal cells. TAMs Tumor-associated macrophages, CAFs Tumor-associated fibroblasts, MDSCs Myeloid-derived suppressor cells, MSCs Mesenchymal stem cells, RTKs Receptor tyrosine kinase inhibitors, VCAM1 Vascular cell adhesion molecule-1. ICAM1 Intercellular cell adhesion molecule-1, GzmB Granzyme B, IDO Indoleamine 2,3 -dioxygenase

Fig. 5

The impact of a healthy lifestyle on the immune system during elimination phase. Mental health, exercise, nutrition, and sleep synergistically enhance the function of the immune system during the elimination phase. GABA Gamma-aminobutyric acid

Fig. 6

The process of counter-immunoediting therapy. Patients are first phenotyped from the initial diagnosis to understand their immune status, followed by the selection of appropriate normalized treatment strategies according to different phenotypes; When the escape phase retrogrades to the equilibrium or elimination phase, the corresponding treatment strategy is selected for further intervention to help the immune system effectively target and kill tumor cells. This approach has the potential to enable patients to achieve a CR or maintain a long-term cure by taking into account the patient's unique immune phenotypes and selecting the most appropriate treatment strategy. RTK Receptor tyrosine kinase inhibitors, TME Tumor microenvironment