ABSTRACT
Interleukin 10 (IL-10) belongs to IL-10 family cytokines that are critical for maintaining the integrity of epithelial tissues, protecting pathogenic infection, and preventing excessive immune responses to damage self. Temporal IL-10 signaling blockade enhances vaccine-induced tumor regression by CD8 + T cells. IL-10, especially pegylated IL-10, mediates tumor regression by expanding tumor-infiltrating CD8 + T cells. Moreover, targeting IL-10 enhances immune checkpoint inhibitor mediated tumor regression. In the current paper, we will review recent advances in this area and discuss the complexity of IL-10 manipulation for cancer therapy.
KEYWORDS:
Introduction
Immunotherapy has been turned into a clinical modality against both cancers and autoimmune diseases.Citation1,Citation2 Immune checkpoint blockade therapies targeting PD-1 and CTLA-4 result in long-lasting immune responses with proven clinical benefits for a fraction of cancer patients, Citation3 although some patients do not respond, and some progress after responding to the initial therapy.Citation4 Cytokine is another prime target for immunotherapy.Citation5 Tumor necrosis factor alpha (TNFα) and interleukin-17 (IL-17) monoclonal antibodies have clinical efficacy against autoimmune diseases such as rheumatoid arthritis and psoriasis;Citation6,Citation7 systemic delivery of IL-2 is effective in solid tumors, such as renal cell carcinoma and melanoma patients.Citation8
Table 1. Key preclinical and clinical results of IL-10 manipulation for cancer therapy
The IL-10 family cytokines consist of IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29.Citation9 They have diverse biological functions, including maintaining the integrity of epithelial layers, promoting innate immune responses against pathogenic infections, facilitating the tissue-healing process in injuries and repressing proinflammatory responses and limiting unnecessary tissue disruptions.Citation9 The receptor structures of IL-10 family cytokines, the signaling pathways, the biological functions and applications for the treatment of cancers, and autoimmune diseases have been reviewed extensively.Citation1,Citation10-17 As for cancer therapy, targeting IL-10 has yet to achieve the similar clinical benefit obtained by the immune checkpoint inhibition therapy. Either blocking IL-10 or systemic administration of IL-10 inhibit tumor growth in animal models or clinical trials, reflecting the complexity and difficulty of targeting IL-10 for cancer therapy. In the current paper, we will review recently published literature in this area and mainly focus on discussing targeting IL-10 signaling for cancer therapies. The potential uses of other IL-10 family members for cancer therapy, such as IL-24 and IFNλ, were described in a recently published paper and will not be discussed in the current paper.Citation11
Vaccination with simultaneous IL-10 signaling blockade better inhibits tumor growth
Immunization and simultaneously blocking IL-10 using IL-10 receptor monoclonal antibodies drastically increase vaccine-induced antigen-specific CD8 + T cell responses, regardless the immunogen is composed of virus-like particles, peptides, soluble antigens, or nucleotides ().Citation10,Citation18-20 The enhanced vaccine-induced T cell responses can also be achieved by using soluble IL-10 receptor,Citation21 peptide-based IL-10 receptor antagonist,Citation22,Citation43 or oligonucleotides.Citation23 Subcutaneous administration of anti-IL-10 receptor antibodies together with a vaccine, instead of intraperitoneal injection of anti-IL-10 antibodies, also elicits stronger antigen-specific CD8 + T cell responses, yet at a much lower magnitude.Citation24 Immunization in conjunction with simultaneous IL-10 signaling blockade better inhibits tumor growth in a prophylactic setting compared with the same vaccination without IL-10 signaling blockade,Citation25 or in a therapeutic setting which was achieved by intraperitoneal administration of anti-IL-10 receptor antibodies.Citation26 These results indicate that IL-10 signaling blockade is beneficial for cancer therapeutic vaccines. Vaccine-induced IL-10 rather than that derived from tumor determines the efficacy of therapeutic vaccination.Citation26 However, when vaccines containing adjuvants that do not induce IL-10, such as the TLR3 ligand poly (I:C) or anti-CD40 agonistic antibodies, anti-IL-10R antibodies will not provide any beneficial effect against tumor growth, due to the lack of IL-10 production by dendritic cells (DC) stimulated by these adjuvants.Citation26 IL-10 is detrimental at the T cell priming stage of an immune response, through the suppression of dendritic cells by inhibiting antigen presentation and reducing MHCI, II, and co-stimulator expression on the membranes of the dendritic cells.Citation13 Therefore, not surprisingly blocking IL-10 signaling on dendritic cell based vaccines generates stronger anti-tumor responses.Citation13
Systemic administration of IL-10 inhibits tumor growth in animal tumor model and clinical trials
Cancer patients often have elevated levels of serum and tumor IL-10,Citation10 high IL-10 level is inversely correlated with the patients’ prognosis.Citation27 However, immune activation was detected when IL-10 was administered in clinical trials, including elevated granzymes and IFNγ in the serum of treated individuals.Citation28 In preclinical tumor models, pegylated recombinant (PEG) murine IL-10 induces rejection of large tumors and metastasesCitation44 through increased CD8 + T cell-mediated immune responses. Depletion of CD4 + T cells did not affect the PEG-IL-10-inflicted tumor control, while preventing migration of T cells to/from the tumor retained the rejection of tumors upon IL-10 treatment.Citation10 In a clinical trial, PEG-IL-10 was well tolerated and had an immunologic and clinical benefit in solid tumors, especially in renal cell carcinoma (RCC) and uveal melanoma.Citation29 PEG-IL-10 induces CD8 + T cell immunity in cancer patients, including elevation of interferon-γ and granzyme B, expansion and activation of intra-tumor CD8 + T cells, and proliferation and expansion of LAG-3+ PD-1+ CD8 + T cells.Citation45 Newly expanded T cell clones were also observed.Citation45
Targeting IL-10 combined with immune checkpoint blockade has synergetic anti-tumor effect
IL-10 and PD-1 execute their biological functions through different signaling pathways.Citation46-47 The IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct.Citation27 Simultaneous blockade of IL-10 and PD-L1 is significantly more effective in restoring antiviral T cell responses than blockade of either alone, and leads to enhanced control of an established persistent viral infection in a murine model of lymphocytic choriomeningitis virus (LCMV).Citation27,Citation31 Tumor antigen-specific CD8 + T cells isolated from the peripheral blood of melanoma patients upregulate IL-10R along with PD-1 upon TCR activation in vitro, IL-10 impedes the expansion of the tumor antigen-specific CD8 + T cells upon antigen stimulation, while IL-10R and PD-1 blockade increase the expansion and functions of the tumor antigen-specific CD8 + T cells.Citation32 Interestingly, CD8+ tumor-infiltrating lymphocytes (TILs) present in metastatic melanoma co-upregulate IL-10R and PD-1Citation32; double blockades of IL-10 and PD-1 increase the proliferation of CD8+ TIL.Citation32 Similarly, treatment of ovarian tumor-bearing mice with PD-1 blocking antibody results in an increase of IL-10 levels in both serum and ascites. While PD-1 blockade or IL-10 neutralization as monotherapies was inefficient, a combination of these two led to improved survival and delayed tumor growth, accompanied by augmented anti-tumor T cell responses and decreased infiltration of immunosuppressive myeloid-derived suppressive cells (MDSCs).Citation33 Not surprisingly, therapeutic vaccination plus PD-1 blockade further improves the efficacy of an HPV16E7 nucleotide vaccine in a TC-1 tumor model.Citation34
On the other hand, combined with anti-PD-1 immune checkpoint blockade, CmAb-(IL10)2, an anti-EGFR antibody conjugated with IL-10 significantly improves antitumor effects in mice with advanced tumors.Citation35 Furthermore, in a multicenter, multicohort, and open-label phase 1b trial, 111 patients with advanced malignant solid tumors refractory to previous therapies were enrolled, 53 received PEG-IL-10 (pegilodecakin) and anti-PD-1 (pembrolizumab or nivolumab) treatment, the objective responses were observed in 12 (43%) of 28 non-small-cell lung cancer, three (10%) of 31 melanoma, and 14 (40%) of 35 renal cell carcinoma, suggesting that PEG-IL-10 plus anti-PD-1 monoclonal antibody (pembrolizumab or nivolumab) could provide a new therapeutic opportunity for previously treated patients with renal cell carcinoma and non-small-cell carcinoma.Citation36
The complexity of targeting IL-10 signaling for cancer immunotherapy
Cancer develops after winning the battle against the immune system.Citation48,Citation37 The tumor microenvironment (TME) establishes along with the cancer development prevents tumor cells from being killed by effector cells, mostly CD8 + T cells and results in the generation of exhausted T cellsCitation5,Citation49 that lack proper T cell functions. The efficiency of immunotherapies, therefore, relies on sufficient functional effector T cells which are able to migrate to tumor and an immunogenic TME.
Most immune-associated hematopoietic cells express IL-10R on their membranes, responding to IL-10 through the IL-10 receptor and subsequent cell signaling pathways. Therefore, the efficacy of IL-10 signaling manipulation,Citation15 either blocking or promoting IL-10 signaling, will depend on the overall responses of all IL-10 receptor-expressing cells.
Systemic blockade of IL-10 signaling with monoclonal anti-IL-10 receptor antibodies has minimal effect on tumor growth except that the tumor cells secrete higher IL-10.Citation38 Combined with an intra-tumor injection of CpG, a toll-like receptor 9 ligand, systemic administration of anti-IL-10 receptor monoclonal antibodies suppresses murine transplant tumor growth through the reversal of tumor-infiltrating antigen-presenting cells.Citation39 Neutralizing the IL-10 produced by vaccine-induced IL-10-secreting dendritic cells,Citation26 or the IL-10-secreting CD4 + T cellsCitation40 in the presence of adjuvants, promotes better vaccine-mediated anti-tumor responses. Therefore, acute inflammation response is necessary for the IL-10 blockade-mediated anti-tumor effect through affecting the IL-10 receptor-expressing APCs. In support of this argument, tumor local blockade of IL-10 and CXCL12, by their gene traps delivered by a nano-delivery system, has an anti-tumor effectCitation41 with improved TME and with reduced immunosuppressive cells, such as M2 macrophages, MDSCs, and PD-L1+ cells. Activated CD4+ and CD8 + T cells, but not naive CD4+ and CD8 + T cells, usually express IL-10 receptors.Citation50 IL-10 blocking antibodies may also act on IL-10 receptor-expressing tumor-infiltrating T cells. How their biological function is affected by the IL-10 signaling blockade is largely unknown. The effects of IL-10 blockade may be minimal or the effect is diluted by newly activated tumor-infiltrating T cells induced through IL-10 signaling blocked antigen-presenting cells. The result that vaccination and simultaneous IL-10 signaling blockade do not change the tumor IL-10 level in a murine TC-1 tumor modelCitation19 seems to support the first argument.
IL-10 is critical for maintaining the integrity of epithelial tissues. IL-10 deficiency leads to chronic inflammatory diseases in the gut.Citation51 However, temporal IL-10 signaling blockade combined with immunization does not cause unwanted side effects.Citation10,Citation52 However, more investigation is required to reveal whether IL-10 signaling blockade hampers the tumor-infiltrating T cell expansion and influences other cells expressing IL-10 receptors, either inside or outside the tumor. Possible side effects of initiating autoimmune diseases also require further investigation.
On the other hand, IL-10, especially pegylated IL-10 suppresses tumor growth in both animal models and clinical trials, although large, controlled clinical trial results remain to be obtained.Citation53 The administrated IL-10 expands and enhances the function of tumor-infiltrating T cells, but IL-10 may also inhibit the function of antigen-presenting cells, either inside the tumor or in the peripheral lymphatic organs, especially when PEG-IL-10 is used. Similarly, IL-10 mediated anti-inflammatory effect through macrophage may be altered. Tumor residential macrophage is one of the most important components in the tumor immune-suppressive environment and promotes tumor expansion and metastasis.Citation54,Citation55 Recent results found that IL-10 inhibits macrophage by reducing lipopolysaccharide-induced glucose uptake and glycolysis, thus to promote oxidative phosphorylation and suppresses mammalian target of rapamycin (mTOR) activity.Citation56 Interestingly, PEG-rIL-10 treatment of tumor-bearing mice reduces intra-tumoral FoxP3+ CD4 + T cells in an IDO-independent manner, and PEG-rIL-10 inhibits TGFβ/IL-2-dependent in vitro polarization of FoxP3+ CD4+ Tregs and potentiates IFNγ+T-bet+CD4 + T cells.Citation57 As most immune-associated hematopoietic cells express IL-10 receptor, secrete and/or respond to IL-10, the effect of IL-10 signaling manipulation on these cells needs to be carefully evaluated.Citation15 To shed light on the complexity of IL-10 signaling blockade, a quantitative proteomic study reveals the enhanced immune response with the blockade of interleukin 10 with anti-IL-10, and anti-IL-10 receptor antibodies in LPS stimulates human U937 cells through different mechanisms.Citation58
Systemic administration of PEG-IL10 showed increased immune cell infiltration and pathological immune responses in normal organs.Citation42 Patients receiving PEG-IL10 also showed adverse events.Citation29 To overcome the potential of side effects of IL-10, an anti-epidermal growth factor receptor antibody (Cetuximab)-based IL-10 fusion protein (CmAb-(IL10)2) was generated and allowed tumor-targeted delivery of IL-10. Potent antitumor effects of CmAb-(IL10)2 with reduced toxicity were observed. The underlying mechanism is by preventing of dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production.Citation35 Expression of IL-10 receptor on dendritic cells is required for preventing the apoptosis of antigen-specific CD8 T cells, mostly activated CD8 + T cells.Citation30
Conclusions and future directions
IL-10 is traditionally recognized as an anti-proinflammatory cytokine secreted by Th2 T cells. IL-10 dampens the magnitude of the immune response to both self and foreign antigens. Therefore, it is not surprising that IL-10 signaling blockade enhances vaccine-induced T cell responses and better prevents tumor growth.Citation41 Exogenous IL-10, especially PEG-IL-10, on the other hand, also leads to tumor regression. The seemingly contradictory IL-10 mediated anti-tumor effect remains to be fully understood. The anti-tumor ability of other members of IL-10 family cytokines also warrants further investigation. It is crucial to understand how IL-10 receptor-expressing cells respond to exogenous IL-10 or IL-10 inhibitors (including IL-10 receptor monoclonal antibodies or other IL-10 inhibitors). How does PEG-IL-10 expand TIL CD8 + T cells? Single-cell RNA sequencing technology defines the immune contexture of tumor for prognosis prediction and immunotherapy.Citation59 Comparative proteomic study reveals the enhanced immune response with the blockade of interleukin 10 with anti-IL-10 and anti-IL-10 receptor antibodies through different pathways.Citation58 The integrative applications of new technologies including transcriptomics, proteomics, metabolomics, and single-cell sequencing will provide more detailed information to understand how tumor as an entire tissue responds to IL-10 manipulation.
Disclosure of potential conflicts of interest
The authors declare that there is no conflict of interest regarding the publication of this paper.
Additional information
Funding
References
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