Systemic immunity in cancer

Abstract

Immunotherapy has revolutionized cancer treatment, but efficacy remains limited in most clinical settings. Cancer is a systemic disease that induces many functional and compositional changes to the immune system as a whole. Immunity is regulated by interactions of diverse cell lineages across tissues. Therefore, an improved understanding of tumour immunology must assess the systemic immune landscape beyond the tumour microenvironment (TME). Importantly, the peripheral immune system is required to drive effective natural and therapeutically induced antitumour immune responses. In fact, emerging evidence suggests that immunotherapy drives new immune responses rather than the reinvigoration of pre-existing immune responses. However, new immune responses in individuals burdened with tumours are compromised even beyond the TME. Herein, we aim to comprehensively outline the current knowledge of systemic immunity in cancer.

Fig. 1. Systemic perturbations to immune organization by the tumour burden.

The peripheral immune landscape is perturbed in many tumour types. The bone marrow, blood, spleen and draining lymph node (dLN) form an immunological network in constant communication during tumour development. a | Bone marrow haematopoiesis skews towards the production of neutrophils and monocytes through increased frequency of haematopoietic stem cells (HSCs) and granulocyte monocyte progenitors (GMPs). In some contexts, this skewing occurs at the expense of dendritic cell precursors which share progenitors, leading to a systemic paucity of dendritic cells that has been shown to be driven by G-CSF stimulating STAT3 signalling while repressing IRF8, as well as through vascular endothelial growth factor (VEGF) decreasing NF-κB signalling. T cell, B cell and plasma cell populations in the bone marrow have also been shown to be decreased. b | During tumour development, bone marrow progenitor pools as well as suppressive immature monocytes and neutrophils are mobilized into circulation in the blood. Systemic increased frequencies of suppressive lymphocyte populations, CD4⁺ regulatory T (T_reg) cells and regulatory B cells are also commonly observed. T_reg cells specifically undergo clonal expansion in the periphery before infiltrating the tumour. Dendritic cell as well as CD8⁺ and CD4⁺ T cell frequencies and T cell receptor (TCR) repertoire diversity are decreased in many tumour contexts. Functional deficits in response to stimuli have been identified in T cell populations. CD4⁺ T cells exhibit decreased signalling responses to IL-6 stimulation, and both CD4⁺ and CD8⁺ T cells produce less IL-2 and IFNγ in response to PMA and ionomycin stimulation. Natural killer (NK) cell cytotoxic potential is also decreased. c | Several alterations observed in the blood have been mirrored in the spleen in mouse models, including accumulation of immature neutrophils, monocytes and semi-mature dendritic cells. Decreased abundance of dendritic cells and T cell populations has also recently been described. d | The tumour dLN has the most direct line of communication with the tumour and is characterized by increased frequency of monocytes and dendritic cells with a decrease of CD8⁺ T cells. Collectively, these observations across many human and mouse tumour models demonstrate that the peripheral immune landscape is shifted towards a suppressive state marked by increases in anti-inflammatory cell types and decreases in key mediators of antitumour immunity. MMP, multipotent progenitor.

Fig. 2. Systemic immune responses in cancer immunotherapy.

Effective responses to immunotherapy drive de novo peripheral immune responses. Schematic illustrating how functional antitumour responses are reliant on immune dynamics outside the tumour microenvironment (TME). a | At baseline, conventional dendritic cells (cDCs) in the TME take up tumour antigen and travel to the draining lymph node (dLN), where they can then transfer antigen to resident cDCs through the formation of direct synapses. T cells in the TME reach states of terminal exhaustion due to chronic stimulation, the harsh environment and immunosuppressive cues. Dysfunctional intratumoural T cells accumulate structurally damaged mitochondria, and upregulate CD103 and CD38 coinciding with irreversible epigenetic remodelling. Thus, effective antitumour responses driven by therapy must rely on another source of functional effector T cells. b | Immunotherapeutic intervention through PD1 and PDL1 checkpoint blockade increases the interaction between cDCs and naive T cells in the dLN, and, alongside CD28 co-stimulation, facilitates the priming and rapid expansion of new T cell clones with new antigen specificities. Checkpoint blockade also leads to the proliferation of existing T cell clones in circulation. These expanding peripheral T cells ultimately infiltrate the TME, and express markers indicative of antigen-specific activation and demonstrate functional cytotoxicity. Productive de novo immune responses can also be achieved through CD40 agonism, which can drive cDC activation in settings resistant to checkpoint blockade and initiate these new T cell responses to replace exhausted intratumoural clones.

Fig. 3. Secondary immune challenges in the context of cancer.

Orthogonal challenges that do not share antigens with the tumour and drive immune responses away from the tumour microenvironment have revealed functional impairments in tumour-burdened hosts. a | Various challenges in tumour-bearing mice, including immunizations, bacterial and viral infections, and a Matrigel plug containing a new antigen not expressed in the tumour have shown blunted CD8⁺ T cell proliferation and differentiation. An impaired antibody response has also been observed in response to immunization. b | Mechanistically, several of these challenges (immunization, bacterial infection and Matrigel plug) have been linked to systemic dendritic cell paucity or impaired activation, described in the draining lymph node (dLN) and spleen. The precise drivers of dendritic cell impairment in cancer are still being investigated, but they involve altered dendritic cell development and apoptosis induced by increased circulating IL-6. Immunotherapeutic interventions that activate dendritic cells (anti-CD40) or increase their abundance (FLT3L) have restored CD8⁺ T cell proliferation and differentiation. cDC, conventional dendritic cell; LCMV, lymphocytic choriomeningitis virus.