Exploring innate immunity in cancer immunotherapy: opportunities and challenges

The recognition of the important role of cancer immunity in tumors has led to the introduction of immunotherapeutic strategies. Most of the immunomodulatory approaches currently being developed engage the adaptive immune system. The clinical approval of checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy has led to considerable success in treating hematologic malignancies.^1–4 However, for the majority of patients with solid tumors, little or no progress has been seen. The efficacy of immunotherapies is limited by the complexities of a diverse set of immune cells and interactions between tumor cells and all other cells in the local microenvironment of solid tumors. A large proportion of immune cells in and around solid tumors derive from the innate arm of the immune system, and using these innate cells against tumors offers an alternative immunotherapeutic option, while current strategies mainly focus on the adaptive arm of the immune system.⁵ In a recent issue of Cell research, Lv et al.⁶ discovered that Mn²⁺ played a critical role in the innate immune sensing of tumors, as Mn-insufficient mice poorly controlled tumor growth and metastasis. Mechanistically, Mn²⁺ promoted dendritic cell (DC) and macrophage maturation and tumor-specific antigen presentation, augmented CD8⁺ T-cell differentiation and activation and NK cell activation, and increased memory CD8⁺ T cells in a cyclic-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent manner, uncovering a critical role of Mn in bridging innate and adaptive immunity for tumor surveillance.

The main components of the innate immune system involve various types of cells of the myeloid lineage, including DCs, monocytes, and macrophages, all of which function as professional antigen-presenting cells (APCs), and innate lymphoid cells, such as natural killer (NK) cells, rely on germline-encoded pattern-recognition receptors (PRRs) and other cell-surface receptors to rapidly detect microbial proteins or membranous molecules on tumor cells to orchestrate downstream inflammatory reactions.⁷ These cells initiate adaptive immune responses while mounting their own effector responses, such as macrophage phagocytosis and the natural cytotoxicity of NK cells.^7,8 Integral to this bridging of innate and adaptive immunity is the ability of APCs to engulf tumor cells via phagocytosis, a cellular process involving target cell recognition, cellular engulfment, and lysosomal digestion that is regulated by receptor–ligand interactions between the target cell and the phagocyte.⁹

Successful cancer immunotherapy using the blockade of immune checkpoints and CAR T cells has largely been framed with the central dogma in which immunotherapies intrinsically target T cells, triggering the tumoricidal potential of the adaptive immune system.^3,4 T cells undoubtedly remain a critical piece of the story; however, T cells are not autonomous in their effector functions. In consideration of this, non-T-cell immune populations, such as innate immune cells, have been identified as potential immunotherapeutic targets (Fig. 1). Cells of the myeloid linage are a major component of immune cell infiltration of tumors, yet current immunotherapies exclusively target the adaptive immune system. The tumor and its milieu often alter the phenotype of myeloid cells toward a protumoral phenotype. Thus, immunotherapies aimed at reversing the protumor phenotype or promoting the antitumor phenotype of innate immune cells represent an attractive antitumor strategy that could act synergistically with current immunotherapies targeting adaptive immunity. Many attempts have been made to improve the capacity of innate immunity to sustain and increase tumor-specific T effector cell numbers and functions, such as using FLT3L, GM-CSF, type I IFNs, IL-2, and IL-15, to induce APC proliferation and maturation or NK cell activation.⁵ Intriguingly, innate immune cells can also be manipulated, such as by T cell-mediated targeting of activating receptors or blocking inhibitory pathways.⁵ Emerging evidence has indicated that innate immune checkpoints, which interfere with the detection and clearance of tumor cells through phagocytosis and suppression of innate immune sensing, also play key roles in tumor-mediated immune escape and might thus be potential targets for cancer immunotherapy.⁹ Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47–signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies.⁹

Fig. 1.

Engaging innate immune cells to boost antitumor immunity for immunotherapy. A diverse set of pattern-recognition receptors (PRRs) detect damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs) or tumor-associated antigens (TAAs), and activate innate immune cells within the TME. These sensors can also be expressed by tumor cells themselves. Multiple PRRs, including cGAS/STING, RIG-I and TLRs, promote the transcription of proinflammatory genes via IRF-3 and NF-κB. These processes result in type I IFN, cytokine, and chemokine production, which supports a cytotoxic antitumor response mediated by effector T cells and NK cells. In addition, DCs in the tumor produce CXCL-9 and CXCL-10, which are two chemokines that are essential for the infiltration of tumor-specific CD8 T cells into the tumor and the killing activity of these cells; these chemokines also induce the recruitment of NK cells, which can sustain T-cell responses. Accordingly, NK cells produce an array of cytokines and chemokines that regulate immune responses. Through the release of CC-chemokine ligand 5 (CCL5), FLT3L, XC-chemokine ligand 1 (XCL1), and XCL2, NK cells promote the recruitment of dendritic cells (DCs) into solid tumors. Finally, CAR NK cells and CAR macrophages can directly kill cancer cells and facilitate antigen presentation to cope with tumor heterogeneity. CAR NK cells can induce the early onset of antitumor activity, followed by the recruitment of T cells through chemokines. CAR macrophages can also remodel the immunosuppressive tumor milieu and further enhance the activation and recruitment of immune cells, such as T cells

Another possible approach involves the use of agonists of innate immune responses. Pathways that were initially shown to contribute to the detection of infections have also been found to participate in the detection of tumor cells. Nucleic acid sensing involves endosomal Toll-like receptors (TLRs) and cytosolic nucleic acid sensors, such as RIG-I-like receptors (RLRs) and STING. Synthetic molecules resembling those induced by infection have been developed to stimulate the innate immune response at the tumor site for therapeutic purposes. This strategy differs from other approaches that require prior identification of cancer antigens (for example, CAR T cells) because it makes use of the endogenous antigen repertoire that is present within the tumor. Synthetically targeting TLRs, STING, and RLRs have shown the ability to control tumors by multiple processes, including the induction of tumor cell death, phagocytosis, the production of type I IFNs, proinflammatory cytokines and T cell-tropic chemokines, NK cytotoxicity, DC maturation, and the promotion of tumor-specific CD8 T cells, thereby ensuring long-term systemic protection.

Following the clinical successes achieved with CAR T-cell therapies, substantial efforts have been applied to exploring the efficacy of CAR non-T cells and the potential advantages these cells offer over their T-cell counterparts. Compared to T cells, NK cells offer many advantages for cancer immunotherapy.^10,11 Given the absence of graft-versus-host disease following the injection of allogenic NK cells, infusions of off-the-shelf umbilical cord blood (UCB)-derived CAR NK cells are being tested in clinical trials against several types of leukemia.¹¹ NK cell lines, as well as primary NK cells from peripheral blood, UCB, or induced pluripotent stem cells, have been used for CAR NK cell production. In addition, CAR NK cells are generating considerable enthusiasm in large part due to their potential to circumvent the life-threatening adverse effects of CAR T cells while recapitulating the robust antitumor effects of CAR T cells.¹¹ Macrophages, as innate myeloid cells, are professional phagocytes that are capable of mediating homeostasis in the adaptive immune system. CAR macrophages are also being generated based on the rationale that macrophages are actively recruited to solid tumors and that macrophages equipped with CAR can be polarized toward an antitumoral phenotype, enhancing the activation and recruitment of immune cells, such as T cells.¹² Therefore, CAR macrophages have the potential to circumvent some of the limitations of CAR T cells in solid tumors: immune cell penetration and the immunosuppressive milieu. These results highlight the role of the innate immune system when considering immunotherapeutic strategies and add another platform to the increasing number of cell therapy modalities to treat solid tumors.

Despite considerable scientific and clinical progress, further studies will need to address several conceptual gaps in our understanding of the dynamic interplay between cancer and immune cells within the tumor milieu following therapeutic intervention. It will be critical to further define the context-dependent roles of innate immune pathways in different tumors and genomic subtypes. Activation of innate immunity can be a “double-edged sword”, which not only plays a critical role in perpetuating these tumor-promoting hallmarks but also in developing antitumor adaptive immune responses to different cancers. For example, STING signaling is active not only in DCs and macrophages but also in T cells. Conversely, the activation of STING in T cells leads to T-cell stress and cell death, which may reduce the clinical outcome of STING agonist-based immunotherapies.¹³ Notably, myeloid cells and innate lymphocytes contribute to both checkpoint efficacy and resistance through both direct and indirect mechanisms. The challenge for researchers and clinicians is to balance the differences. Finally, selective context-specific targeting of the innate immune system has the potential to become a cornerstone of immunotherapeutic strategies for the treatment of solid tumors.

Competing interests

The authors declare no competing interests.