Perspectives of Immune Suppression in the Tumor Microenvironment Promoting Oral Malignancy

Kondoh, Nobuo; Mizuno‐Kamiya, Masako; Takayama, Eiji; Kawati, Harumi; Umemura, Naoki; Yamazaki, Yutaka; Mitsudo, Kenji; Tohnai, Iwai

doi:10.2174/1874210601812010455

Cited by 9 publications

(7 citation statements)

References 104 publications

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“…MDSCs expand in chronic or tumor-associated inflammations, exerting immunosuppressive functions. The generation of MDSCs is promoted by pro-inflammatory cytokines, including VEGF, IL-1β, IL-6, IL-17, and TNF-α [ 100 ].…”

Section: Crosstalk Among Cancer and Stromal Cellsmentioning

confidence: 99%

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

Kondoh

Mizuno‐Kamiya

2022

Cancers

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HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role as an anti-tumor regulator against HNSCCs; however, IFN-γ also drives programmed death-ligand (PD-L) 1 expression to promote cancer stem cells. Interleukin (IL)-2 promotes the cytotoxic activity of T cells and natural killer cells; however, endogenous IL-2 can promote regulatory T cells (Tregs), resulting in the protection of HNSCCs. In this report, we first classified and mentioned the immune modulatory aspects of pro-inflammatory cytokines, pro-/anti-inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. In the TME of HNSCCs, pro-tumoral immune modulation is mediated by stromal cells, including CAFs, MDSCs, pDCs, and TAMs. Therefore, we evaluated the functions of cytokines and chemokines that mediate the crosstalk between tumor cells and stromal cells. In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. We therefore evaluated the possibility of chemokines mediating lymph node metastases in HNSCC patients. We also mention therapeutic approaches using anti-tumoral cytokines or immunotherapies that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. We finally discuss modulation by HPV infection upon HNSCC phenotypes, as well as the prognostic significance of serum cytokine levels in HNSCC patients.

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Section: Crosstalk Among Cancer and Stromal Cellsmentioning

confidence: 99%

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

Kondoh

Mizuno‐Kamiya

2022

Cancers

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“…The immunological characteristic of this stage is that cancer cells secrete a series of signal molecules that allow the immune system to sleep, disabling anticancer activities. Malignant solid tumor also secretes signal molecules to recruit immature immune cells and other cells to enter the tumor, then educate, or reprogram them to become immune suppressor cells (such as MDSC, Treg, TAM and CAF) that could secrete immunosuppressive molecules (such as IL-10 and TGF-β), therefore forming the immunosuppressive microenvironment [11][12][13]18]. All of these are intrinsically based on the fact that cancer cells can secrete a series of signal molecules that could inhibit the immune system.…”

Section: Systemic Ecological Counterattack Therapymentioning

confidence: 99%

“…In general, the hot tumors present higher response rates to checkpoint inhibitors, while cold tumors (such as glioblastomas) present low mutation load and rare infiltrating immune effector cells, and are thus largely resistant to multiple immune checkpoint blockade therapies [14][15][16][17]. Besides expressing more checkpoint molecules on effector T cells, TME is infiltrated with various immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) as well as their effector molecules, such as IL-10 and TGF-β, to form a strong immune suppressive network or TME [11][12][13]18] within solid tumors. Therefore, checkpoint inhibitors alone could not systemically counteract this immunosuppressive network or microenvironment.…”

Section: Introductionmentioning

confidence: 99%

The mechanisms of action of Plasmodium infection against cancer

Chen

et al. 2021

Cell Commun Signal

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Our murine cancer model studies have demonstrated that Plasmodium infection activates the immune system that has been inhibited by cancer cells, counteracts tumor immunosuppressive microenvironment, inhibits tumor angiogenesis, inhibits tumor growth and metastasis, and prolongs the survival time of tumor-bearing mice. Based on these studies, three clinical trials of Plasmodium immunotherapy for advanced cancers have been approved and are ongoing in China. After comparing the mechanisms of action of Plasmodium immunotherapy with those of immune checkpoint blockade therapy, we propose the notion that cancer is an ecological disease and that Plasmodium immunotherapy is a systemic ecological counterattack therapy for this ecological disease, with limited side effects and without danger to public health based on the use of artesunate and other measures. Recent reports of tolerance to treatment and limitations in majority of patients associated with the use of checkpoint blockers further support this notion. We advocate further studies on the mechanisms of action of Plasmodium infection against cancer and investigations on Plasmodium-based combination therapy in the coming future.

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“…As we have already reported, the immunosuppressive efficacy of the OSCC milieu in the early stage is developed without reliance on the induction of myeloid derived suppressor cells (MDSCs) [47]. In the early stage, as represented by mouse OSCC, Sq-1979 cells, IL-1α from OSCC cells can functionally enhance immune suppressive activity of mesenchymal stromal cells which are directly contacted with activated spleen cells [48].…”

Section: Function Of Inflammatory Modulatormentioning

confidence: 99%

“…In the early stage, as represented by mouse OSCC, Sq-1979 cells, IL-1α from OSCC cells can functionally enhance immune suppressive activity of mesenchymal stromal cells which are directly contacted with activated spleen cells [48]. In contrast, MDSCs are strongly induced in mice with metastasized, advanced OSCC cells [47]. In fact, IL-1 may specifically contribute to the development of early-stage OSCCs, since IL-1 receptor antagonist (IL1RN) is markedly downregulated in early OSCCs compared to premalignant lesions and advanced OSCCs [49].…”

Section: Function Of Inflammatory Modulatormentioning

confidence: 99%

Immunomodulatory aspects in the progression and treatment of oral malignancy

Kondoh

Mizuno‐Kamiya

Umemura

et al. 2019

Japanese Dental Science Review

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Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.

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Perspectives of Immune Suppression in the Tumor Microenvironment Promoting Oral Malignancy

Cited by 9 publications

References 104 publications

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

The mechanisms of action of Plasmodium infection against cancer

Immunomodulatory aspects in the progression and treatment of oral malignancy

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