The success of checkpoint inhibitors has accelerated the clinical implementation of a vast mosaic of single agents and combination immunotherapies. However, the lack of clinical translation for a number of immunotherapies as monotherapies or in combination with checkpoint inhibitors has clarified that new strategies must be employed to advance the field. The next chapter of immunotherapy should examine the immuno-oncology therapeutic failures, and consider the complexity of immune cell–cancer cell interactions to better design more effective anticancer drugs. Herein, we briefly review the history of immunotherapy and checkpoint blockade, highlighting important clinical failures. We discuss the critical aspects — beyond T cell co-receptors — of immune processes within the tumour microenvironment (TME) that may serve as avenues along which new therapeutic strategies in immuno-oncology can be forged. Emerging insights into tumour biology suggest that successful future therapeutics will focus on two key factors: rescuing T cell homing and dysfunction in the TME, and reappropriating mononuclear phagocyte function for TME inflammatory remodelling. New drugs will need to consider the complex cell networks that exist within tumours and among cancer types.
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The authors thank M. Saunders for scientific editing of the Review and L. Vornholz for his intellectual and literary contribution to the section on T cell homing.
The authors declare no competing interests.
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- Tumour-infiltrating lymphocytes
(TILs). T cells bearing either CD4 or CD8 as well as B cells that are found in the tumour.
- Cytotoxic T lymphocytes
(CTLs). T cells bearing the CD8 co-receptor that kill target cells by cytotoxic cytokine secretion, induction of apoptosis or induction of perforin–granzyme cytotoxicity.
- T helper 1 cells
(TH1 cells). A specialized population of CD4+ T cells. They are important for immune responses against bacteria and viruses that invade cells, and are characterized by their production of interferon-γ.
- Regulatory T cells
(Treg cells). FOXP3-expressing T cells that act indirectly to rein in the responses of effector T cells.
- Progression-free survival
(PFS). The length of time during and after treatment that a patient lives with the cancer but it does not get worse.
- Overall survival
(OS). The length of time from either the date of diagnosis or the start of treatment that patients remain alive.
- Antibody-dependent cell-mediated cytotoxicity
(ADCC). An immune effector function that occurs when antigen–antibody complexes bind to the Fc receptors of immune cells to trigger degranulation and destroy the entity.
- Complement-dependent cytotoxicity
(CDC). The destruction of cells mediated by complement, which is a system of more than 30 soluble and membrane-bound proteins that act through a tightly regulated cascade of protein cleavage events to assemble the membrane attack complex in a target cell membrane.
- Objective response rate
(ORR). The proportion of patients who have a partial or complete response to a therapy.
- Chimeric antigen receptor (CAR) T cells
T cells that are genetically engineered to express a novel chimeric T cell receptor containing a portion of an antibody that recognizes an antigen on targeted tumour cells combined with the internal signalling apparatus of the T cell.
- Adoptive cell transfer
The transfer or reinfusion of cells, most commonly by intravenous infusion.
- Cancer-associated fibroblasts
Spindle-shaped cells within the tumour stroma that build up and remodel the extracellular matrix to support cancer growth.
- Cytokine release syndrome
Pathology induced by a large, rapid release of cytokines into the blood by immune cells.
- Exhausted T cells
(Tex cells). T cells that are phenotypically characterized by a progressive loss of effector function due to prolonged antigenic stimulation, such as occurs in chronic infections or cancer.
- Common γ-chain
Cytokine receptor chain CD132, encoded by IL2RG; this chain is shared by the signalling complexes associated with receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
- Cancer testis antigens
Proteins that are normally expressed solely in spermatogonia and spermatocytes but become aberrantly expressed in cancer cells owing to alterations to cancer cell methylomes.
- TCR T cell
A T cell that has been genetically engineered to express a T cell receptor (TCR) with known specificity. In cancer, TCR T cells have been used to target known tumour antigens.
- Angiogenic switch
A temporally and spatially restricted event during tumour progression in which proangiogenic factors facilitate the development of new capillary growth. These new vessels subsequently facilitate additional nutrient and waste exchange within the tumour to facilitate more rapid tumorigenesis.
The removal of dead and dying apoptotic cells by professional and non-professional phagocytes.
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Kubli, S.P., Berger, T., Araujo, D.V. et al. Beyond immune checkpoint blockade: emerging immunological strategies. Nat Rev Drug Discov (2021). https://doi.org/10.1038/s41573-021-00155-y