Migrating into the Tumor: a Roadmap for T Cells

Cancer immunotherapy is a rapidly evolving field. Despite promising results, long-lasting response rates remain around 20–40%. The immune cell landscape in tumors is heterogeneous across patients and can influence prognosis and outcome of immunotherapy. It is important to investigate mechanisms that underlie migration of immune cells into the TME. Drugs are being tested in preclinical models and clinical trials that can manipulate the immune cell landscape within the TME. These can be used as monotherapy, but more likely in combination with other therapies. Tumors can be divided into ‘hot’ (T cell inflamed) or ‘cold’ (T cell noninflamed) according to the presence of immune cells. In this review, we discuss variables that influence T cell migration into the tumor microenvironment. Chemokines can attract T cells to the tumor site and tumor intrinsic pathways can influence the composition of local chemokines. Tumor-induced vasculature can hamper T cell migration. Other immune cells and tumor-derived molecules can block T cell proliferation and survival. It is important to better understand these mechanisms in order to target them therapeutically. Enhancing T cell infiltration may increase response rates to immunotherapy and increase survival. Tumors can be divided into ‘hot’ (T cell inflamed) or ‘cold’ (T cell noninflamed) according to the presence of immune cells. In this review, we discuss variables that influence T cell migration into the tumor microenvironment. Chemokines can attract T cells to the tumor site and tumor intrinsic pathways can influence the composition of local chemokines. Tumor-induced vasculature can hamper T cell migration. Other immune cells and tumor-derived molecules can block T cell proliferation and survival. It is important to better understand these mechanisms in order to target them therapeutically. Enhancing T cell infiltration may increase response rates to immunotherapy and increase survival. small protein molecules that attract (immune) cells expressing the binding receptors. CCL and CXCL distinguish different chemokines based on the cysteine residue. In CCL the two cysteines are adjacent whereas in the CXCL they are separated by an amino acid. effector cells of the adaptive immune system and are able to eliminate target cells upon stimulation. CTLs are characterized by expression of the CD8 receptor next to the CD3 molecule. the main type of APCs in the body. DCs take up antigen and present it to T cells in order to initiate an adaptive immune response. group of polymorphonuclear immune cells: neutrophils, eosinophils, and basophils. specialized form of blood vessels that facilitate leukocyte migration to lymph nodes. HEV can also form in the TME. collective term for therapies that enhance the body’s own immune system/immune response to fight cancer. The most well-known therapies are antibody-based immunotherapies, and are the checkpoint inhibitors targeting CTLA-4 (ipilimumab) and PD-1 (pembrolizumab and nivolumab). Examples of cell-based immunotherapies are DC vaccination, adoptive T cell transfer, and chimeric antigen receptor T cell therapy. immune cells important in innate immunity (phagocytosis), which also play a role in adaptive immunity by recruitment of other immune cells that can also act as APCs. immune cells from the myeloid lineage present in tumors that can suppress the antitumor effects of T cells. a subset of T cells that facilitates different processes in immune reactions. T-helper cells are mainly characterized by the expression of the CD4 receptor next to the CD3 molecule. can downregulate or inhibit the T cell-mediated immune response. It is beneficial in preventing autoimmunity but can facilitate immune evasion in cancer. form adjacent to sites of inflammation and have all the features of lymph nodes, to facilitate a local adaptive immune response. defines the non-neoplastic cellular environment of a tumor, including blood vessels, immune cells, fibroblasts, extracellular matrix, cytokines, chemokines, and other active compounds. cytokine that induces angiogenesis.