Figure 1. Immunomodulatory monoclonal antibodies and armoured chimeric antigen receptor (CAR) T cells overcome immune suppression.

a | Overview of the immune inhibitory molecules that compromise endogenous T–cell antitumour activity. T cells are susceptible to immune inhibitory factors associated within the microenvironment that prevent their full antitumour activity. Such factors include cell surface proteins (such as programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2)) and cytokines (such as TGF-β and IL-10). Regulatory T (T_REG) cells are representative of inhibitory cellular components of the tumour microenvironment (TME), which also include myeloid-derived suppressor cells, tumour-associated macrophages and other cell types non-depicted. b | Similarly to endogenous T cells, CAR T cells are susceptible to immune inhibitory factors present in the TME. c | Immunomodulatory monoclonal antibodies can be used to overcome local immunosuppression by either activating stimulatory receptors (such as TNFRSF9 (4-1BB) or OX40), or blocking suppressive receptors (for example, programmed cell-death 1 (PD-1) or cytotoxic T-lymphocyte antigen 4 (CTLA-4)). d | Armoured CAR T cells are engineered to express proteins that overcome immunosuppression associated with the TME (such as CD40L, IL-12 or TNFSF9 (4-1BBL)). Ag, antigen; APC, antigen-presenting cell; CD40L, CD40 ligand; Cy, cyclophosphamide; DC, dendritic cell; Flu, fludarabine; GITR, glucocorticoid-induced TNFR family related protein; GITRL, GITR ligand; HMGB1, high mobility group 1 protein; LAG-3, lymphocyte activation gene-3; PSer, phosphatidyl serine; scFv, single-chain variable fragment; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; TIL, tumour -nfiltrating lymphocyte; TIM-3, T cell immunoglobulin and mucin domain 3.