Tumor Microenvironment: Immunosuppressive Cells

TAMs express indoleamine 2,3-dioxygenase (IDO), which depletes L-tryptophan through kynurenine production. This metabolic pathway inhibits the activity of CD4⁺ and CD8⁺ T cells and natural killer (NK) cells, while promoting the differentiation of regulatory T cells (Tregs), thereby supporting tumor immune evasion.

TAMs express HLA-E and HLA-G, which engage inhibitory receptors on T cells and NK cells, suppressing their cytotoxicity, proliferation, and cytokine production. HLA-G additionally induces tolerogenic dendritic cells, which drive Treg development, further promoting an immunosuppressive microenvironment.

TAMs can express B7-1/CD80, B7-2/CD86, PD-L1, and B7-H4 that bind to co-inhibitory receptors and suppress T cell activation, proliferation, and cytokine production. TAMs also induce T cell apoptosis via Fas L and TRAIL interactions with their T cell-expressed receptors.

TAMs contribute to immunosuppression by secreting IL-10 and TGF-β1, which inhibit effector T cell functions, promote regulatory T cell expansion, impair NK cell activity, and suppress dendritic cell maturation. They also produce prostaglandin E2 (PGE₂) that further inhibits NK and T cell cytotoxicity, promotes MDSC expansion, and skews immune responses toward immunosuppressive phenotypes. Factors secreted by TAMs not only inhibit the anti-tumor immune response, but also drive tumor cell proliferation, angiogenesis, invasion, and metastasis.

TAMs promote immune evasion by expressing SIRP-α, which interacts with overexpressed tumor cell CD47 to deliver a “don’t eat me” signal that inhibits phagocytosis.

TAMs indirectly suppress anti-tumor immunity by secreting chemokines that recruit regulatory T cells, which then inhibit effector T cells, NK cells, and antigen-presenting cells (APCs) through diverse immunosuppressive mechanisms.

Tregs suppress T cell responses by secreting immunosuppressive cytokines such as TGF-β1, IL-10, and IL-35, which inhibit Teff cell differentiation, proliferation, activation, and cytokine production, while promoting conversion to immunosuppressive phenotypes. Additionally, membrane-bound LAP-TGF-β1 and Galectin-1 induce Teff cell growth arrest and apoptosis through both soluble and contact-dependent mechanisms.

Cytokines secreted by Tregs including TGF-β1, IL-10, and IL-35 induce infectious tolerance by converting activated Tconv cells into regulatory cell phenotypes. TGF-β promotes FoxP3⁺ Tregs, IL-10 drives Tr1 cells, and IL-35 induces iTregs, thereby amplifying immunosuppression within the tumor microenvironment and facilitating tumor immune evasion.

Tregs suppress effector T cells by depleting local IL-2 via high CD25/IL-2 Rα expression, causing IL-2 deprivation-induced apoptosis.

Tregs also inhibit Teff cell proliferation and IL-2 synthesis by directly transferring inhibitory cAMP through the gap junctions of Teff cells. 

Tregs express CD39 and CD73 to degrade ATP/ADP into adenosine, which inhibits dendritic cell maturation, suppresses Teff and NK cell functions via A2a/A2b receptor signaling, and promotes both a tolerogenic dendritic cell phenotype and enhanced Treg numbers and suppressive activity.

Tregs contribute to immunosuppression by secreting granzymes, particularly granzyme B, which mediates Teff cell apoptosis primarily through perforin-dependent pathways, with some evidence for perforin-independent mechanisms. Tregs also induce cytolysis of B cells, NK cells, and CD8⁺ T cells through granzyme B and perforin-dependent pathways.

Tregs indirectly suppress Teff cells by using CTLA-4 to downregulate dendritic cell expression of the co-stimulatory molecules, B7-1/CD80 and B7-2/CD86. Binding of CTLA-4 and CD80 or CD86 also triggers the production of indoleamine 2,3-dioxygenase (IDO) by dendritic cells, generating pro-apoptotic metabolites that suppress Teff cell activity. LAG-3 expressed by Tregs binds to MHC class II on immature dendritic cells, thereby blocking their maturation and limiting T cell activation.

MDSCs suppress anti-tumor immunity by depleting key amino acids necessary for T cell proliferation and functions. Increased uptake and metabolism of L-arginine via high levels of ARG1 activity in MDSCs leads to low levels present in the microenvironment, resulting in reduced expression of TCR-CD3 zeta and T cell proliferative arrest. Cystine is also sequestered by MDSCs, limiting its ability to be taken up by APCs and subsequently reduced and exported as cysteine to be provided to T cells during antigen presentation. This compromises T cell activation, proliferation, and differentiation. In the presence of MDSCs, L-tryptophan levels are also reduced through indoleamine 2,3-dioxygenase (IDO)-mediated degradation by the kynurenine pathway, which inhibits the proliferation and activity of CD4⁺ and CD8⁺ T cells and natural killer (NK) cells and promotes the differentiation of regulatory T cells (Tregs).

MDSCs inhibit anti-tumor immunity by producing reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hydrogen peroxide, peroxynitrite, and nitric oxide are produced by MDSCs via NADPH oxidase, ARG1, and iNOS. Collectively, these molecules impair T cell activation, proliferation, and migration, and induce apoptosis, and nitration or nitrosylation of multiple target molecules including TCR, CD3, CD8, and CCL2, which inhibits T cell activation and intra-tumoral migration.

MDSCs suppress T cell functions by expressing PD-L1, Fas Ligand, and Galectin-9, which engage T cell receptors PD-1, Fas/CD95, and Tim-3, respectively, leading to T cell exhaustion or apoptosis depending on the ligand-receptor interaction.

MDSCs produce IL-10 and TGF-β1 which suppress effector T cell activation, differentiation, proliferation, and cytokine production while promoting suppressive T cell expansion. TGF-β1 induces FoxP3⁺ regulatory T cells, while IL-10 promotes the conversion of activated conventional T cells to IL-10-, TGF-β1-secreting Tr1 cells. Additionally, TGF-β1 down-regulates the expression of NKG2D and NKp30 on NK cells and CD8⁺ T cells, reduces NK cell proliferation and cytotoxicity, skews macrophages toward an M2 phenotype, and inhibits dendritic cell maturation, migration, co-stimulation, and IL-12 production.

MDSCs inhibit T cell activation by expressing ADAM17, a protease that cleaves L-Selectin/CD62L on naïve T cells, preventing their homing from the blood and lymphatics to the lymph nodes where activation occurs.

MDSCs express CD39 and CD73 to generate immunosuppressive extracellular adenosine, which inhibits effector T, NK, and NKT cell functions, promotes Treg expansion and suppressive activity, and prevents dendritic cell maturation and pro-inflammatory cytokine production via A2a/A2b receptor signaling. MDSCs also produce PGE₂ through the up-regulated expression of COX-2 and PGES1. PGE₂ signals through receptors expressed on the surface of MDSCs, enhancing their own suppressive activity and expansion. PGE₂ also inhibits NK cell cytotoxicity, dendritic cell differentiation, IL-2 signaling, and Th1/CD8⁺ T cell responses.

MDSCs enhance their own accumulation and migration via an autocrine loop where secreted S100A8/S100A9 proteins bind to RAGE and other glycoprotein receptors on MDSCs, driving their accumulation and recruitment to the tumor microenvironment.

Tolerogenic DCs promote the differentiation and expansion of Tregs, which in turn inhibit the activation and function of effector immune cells, creating an environment that favors tumor immune evasion. This process is often supported by high expression of immunosuppressive enzymes like indoleamine 2,3-dioxygenase (IDO), which contributes to Treg induction and function.

By releasing cytokines such as IL-10 and TGF-β1, tolerogenic DCs actively suppress inflammation and limit the activation of effector T cells and other immune cells, thereby dampening protective anti-tumor immunity.

Tolerogenic DCs express checkpoint ligands like PD-L1 that engage inhibitory receptors on T cells, leading to reduced T cell activation, proliferation, and cytokine production within the tumor microenvironment.

By presenting antigens in a tolerogenic context characterized by low expression of co-stimulatory molecules such as B7-1/CD80 and B7-2/CD86, tolerogenic DCs fail to adequately activate naive T cells, resulting in poor priming and suboptimal anti-tumor immunity.

Through multiple signals, including antigen presentation with low levels of co-stimulatory molecule expression, tolerogenic DCs induce a state of T cell unresponsiveness or tolerance to tumor antigens, thereby limiting effective immune targeting of cancer cells.

Tolerogenic DCs reduce pro-inflammatory signals that would normally promote anti-tumor responses, further shifting the tumor microenvironment towards immunosuppression.

Tolerogenic DCs facilitate the accumulation and function of MDSCs, which synergize to suppress T cell activity and sustain an immunosuppressive niche within tumors.

CAFs produce dense ECM proteins like collagen and fibronectin, which increase stromal stiffness and create a mechanical barrier preventing T cell migration into the tumor core.

CAFs release cytokines (e.g., TGF-β, IL-6) and chemokines that suppress T cell activation or attract immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).

CAF-derived factors shift the composition of immune cell infiltration in the tumor microenvironment toward immunosuppressive phenotypes, which indirectly limits the presence and function of effector T cells within the tumor.