Exploiting innate immunity for cancer immunotherapy

Abstract

Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.

Keywords: Cancer immunotherapy; Chimeric antigen receptor; Dendritic cell; Innate immunity; Macrophage; Myeloid-derived suppressor cell; Natural killer cell; Neutrophil.

Fig. 1

DC-targeted cancer therapies. a The maturation of DCs. In the TME, genomic instability, mitochondrial dysfunction, oxidative stress, and conventional antitumor regimens could support DC maturation by inducing DNA damage and activating cytosolic DNA sensing signaling, such as cGAS/STING/IFN-I pathway. Besides, In the presence of damage-associated molecular patterns from stressed or injured cancer cells, these immature DCs are activated by various PRR pathways. Additionally, chemotherapy and radiotherapy could promote DC maturation by inducing the ICD of cancer cells. DAMPs released during ICD stimulate DC maturation and improve DC functions: ATP facilitates DC recruitment and activation, CRT enhances cancer antigen engulfment, and HMGB1 improves antigen presentation of DCs. b DC-targeted cancer therapies. DC-targeted strategies mainly consist of agonists for DC differentiation, expansion, and activation, blockade of immunoinhibitory signals, and DC vaccines. Abbreviations: DC, dendritic cell; ICD, immunogenic cell death; ATP, adenosine triphosphate; CRT, calreticulin; HMGB1, high-mobility group box 1. Adapted from Yi et al. 2022 [62].

Fig. 2

The protumor activities of TAMs and TAM-targeted cancer therapies. a The protumor properties of TAMs. TAMs are commonly set in the protumor M2-like phenotype and have substantial influences on tumor initiation and progression. On the one hand, TAM-derived soluble molecules directly suppress the functions of tumor-infiltrating T cells and NK cells. Besides, autocrine IL-10 and TNF-α stimulate PD-L1 upregulation on TAMs. Also, TAMs directly suppress the antitumor immune response by recruiting Tregs and supporting their differentiation. On the other hand, TAMs also promote tumor progression in immune-independent ways, including tumor initiation and growth, angiogenesis, stemness, EMT, and distant metastasis. b TAM-targeted therapies. TAMs could be harnessed by targeting their recruitment, activation, immune checkpoint pathways, and metabolism. Besides, macrophage-based cell therapies, such as nanoparticle-loaded monocytes, CAR-M, and genetically engineered hematopoietic progenitors, also show potent antitumor activities. Abbreviations: TAM, tumor-associated macrophage; EMT, epithelial-mesenchymal transition; CSF1, colony-stimulating factor 1; CSF1R, CSF1 receptor; TLR, Toll-like receptor; STING, Stimulator of interferon genes; LILRB, Leukocyte immunoglobulin-like receptor B; SIRPα, Signal regulatory protein-α; IDO, Indoleamine 2,3-dioxygenase; CAR, Chimeric antigen receptor

Fig. 3

MDSC-mediated T cell suppression and MDSC-targeted therapies. a MDSC-mediated T cell suppression. Although MDSCs have been implicated in undermining the functions of multiple immune cells, their main targets are T cells. MDSCs cause immune suppression by upregulating TGF-β, IL-10, IDO, iNOS, ARG1, ROS, PD-L1, and depleting cystine and cysteine in the TME. Besides, the ADAM17 on MDSCs exerts immunosuppressive effects by downregulating L-selectin (T cell homing receptor) on naïve T cells. b MDSC-targeted therapies can be categorized into four groups: suppressing the recruitment and expansion of MDSCs; facilitating the differentiation of MDSCs into mature myeloid cells; counteracting the functions of MDSCs; and directly depleting MDSCs. Abbreviations: MDSC, myeloid-derived suppressor cell; ASC, asc­type amino acid transporter; CAT-2B, cationic amino acid transporter 2B; Xc⁻, cystine-glutamate transporter; IDO, indole-2,3 dioxygenase; NO, nitric oxide; iNOS, inducible nitric oxide synthase; TCR, T cell receptor; ROS, reactive oxygen species

Fig. 4

Interaction between NK cell and the TME. Schematic diagram depicting primary receptors expressed by NK cells and their corresponding ligands on tumor cells or cytokines in the TME. Activating stimulative receptors triggers an intracellular signaling cascade that activates NK cells and vice versa. The two factors dynamically modulate the behavioral pattern of NK cells, whose disequilibrium may lead to immune evasion or clearance. Abbreviations: NK cell, natural killer cell; TME, tumor microenvironment; Ecto-CRT, ecto-calreticulin; A2AR, A2a adenosine receptor; ACVR1, activin receptor type 1

Fig. 5

NK cell-based therapeutic strategies. a NK cell-based therapeutic strategies could enhance multiple biological processes, including trafficking, activation, tumor-killing activity, and NK cell-mediated secondary adaptive immune priming. b NK cell-based therapeutic strategies. The green box denotes the biological process targeted by the corresponding strategy, while the red box denotes the biological process not involved in the corresponding strategy. Abbreviations: ADCC, natural killer cell-mediated antibody-dependent cellular cytotoxicity; CAR, chimeric antigen receptor

Fig. 6

Harnessing innate immunity to improve antitumor immune response. The involvement of innate immunity is crucial for initiating and sustaining adaptive immunity, and it plays a significant role in the overall cancer-immunity cycle. When a tumor is detected, innate immune cells are activated, leading to the enhancement of their effector functions and the destruction of tumor cells. Apart from directly killing tumor cells, innate immune cells participate in priming, expanding, and infiltrating tumor-specific T-cells. Manipulating innate immunity by therapeutic strategies could effectively stimulate antitumor immune response and overcome immune evasion. Abbreviations: DC, dendritic cell; TAM, tumor-associated macrophage; NK cell, natural killer cell; MDSC, myeloid-derived suppressor cell; TME, tumor microenvironment; TCR, T cell receptor; MHC, major histocompatibility complex