Tumor microenvironmental influences on dendritic cell and T cell function: A focus on clinically relevant immunologic and metabolic checkpoints

Abstract

Cancer immunotherapy is fast becoming one of the most promising means of treating malignant disease. Cancer vaccines, adoptive cell transfer therapies, and immune checkpoint blockade have all shown varying levels of success in the clinical management of several cancer types in recent years. However, despite the clinical benefits often achieved by these regimens, an ongoing problem for many patients is the inherent or acquired resistance of their cancer to immunotherapy. It is now appreciated that dendritic cells and T lymphocytes both play key roles in antitumor immune responses and that the tumor microenvironment presents a number of barriers to the function of these cells that can ultimately limit the success of immunotherapy. In particular, the engagement of several immunologic and metabolic checkpoints within the hostile tumor microenvironment can severely compromise the antitumor functions of these important immune populations. This review highlights work from both preclinical and clinical studies that has shaped our understanding of the tumor microenvironment and its influence on dendritic cell and T cell function. It focuses on clinically relevant targeted and immunotherapeutic strategies that have emerged from these studies in an effort to prevent or overcome immune subversion within the tumor microenvironment. Emphasis is also placed on the potential of next‐generation combinatorial regimens that target metabolic and immunologic impediments to dendritic cell and T lymphocyte function as strategies to improve antitumor immune reactivity and the clinical outcome of cancer immunotherapy going forward.

Preoperative Controlling Nutritional Status (CONUT) score predicts short-term outcomes of patients with gastric cancer after laparoscopy-assisted radical gastrectomy

“…The condition of hypoalbuminaemia suggests that the body is in a stage of hypercatabolism, which is prevalent amongst cancer patients, especially those with cachexia. Lymphocytes are important cellular components of the human immune response system that help to fight tumours by inhibiting cancer cell proliferation, invasion and migration [ 30 ]. Saka et al [ 31 ] reported that T cell exhaustion was closely associated with poor prognosis in cancer.…”

Analysis and Augmentation of the Immunologic Bystander Effects of CAR T Cell Therapy in a Syngeneic Mouse Cancer Model

“…One hypothesis to explain these findings is the highly immunosuppressive microenvironment of solid tumors, which impedes endogenous T cell function, 28 , 29 , 30 prevents efficient DC activation, 31 and promotes the expansion of immunosuppressive Tregs. 29 , 32 To assess whether these factors might account for the lack of bystander effects we were seeing in our model, we first blocked the inhibitory T cell receptors PD-1 and CTLA-4, given their known ability to inhibit T cell activation, leading to reduced proliferation, cytokine production, and T cell death.…”

“… 37 T cell cross-priming—a process in which DCs cross-present exogenous antigens to CD8 T cells, resulting in CD8 T cell activation—is critical in generating endogenous anti-tumor CD8 T cell immunity. 31 Despite the presence of DCs in the TME, it appears that tumor-associated DCs are often defective in their differentiation and activation and are poor stimulators of immune responses. 37 We hypothesized that agents capable of activating DC might thus augment CAR-induced antigen cross-presentation and stimulate endogenous anti-tumor T cells and bystander effects.…”

Preoperative Controlling Nutritional Status (CONUT) Score Predicts Short-Term Outcomes of Patients with Gastric Cancer after Laparoscopy-Assisted Radical Gastrectomy

“…The condition of hypoalbuminemia suggests that the body is in a stage of hypercatabolism, which is prevalent among cancer patients, especially those with cachexia. Lymphocytes are important cellular components of the human immune response system that help to ght tumours by inhibiting cancer cell proliferation, invasion and migration 30 . Saka et al 31 reported that the exhaustion of T cells was closely associated with poor prognosis in cancer.…”