Dendritic cells and cancers
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P214-215
2025-12-07
72
The DC-mediated events leading to a successful antitumor immune response can be summarized as (1) DC access to tumor antigens in the tumor microenvironment (TME); (2) DC activation in response to DAMPs in the TME; (3) tumor antigen uptake by DCs; (4) DC migration to LNs; (5) cross-presentation of tumor antigens to T cells, activating tumor-specific CD8+ cytotoxic T cells (CTL); (6) trafficking of CTL to TME; and (7) tumor cell killing by CTL (Fig. 1). As they excel at cross-presentation, the cDC1 subset of DCs is particularly important for eliciting antitumor CTL responses. Notably, CD4+ T cells also play a crucial role in establishing antitumor immunity by enhancing the efficacy of CTL and directing sustained antitumor immune responses. Moreover, tumor-specific CD4+ T cells may also directly exert cytotoxic function.
Fig1. IMMUNE ESCAPE MECHANISMS EXPLOITED BY TUMORS. Summary of DC-mediated events leading to a successful antitumor immune response (left): DCs are recruited to the tumor microenvironment (TME) in response to CCL5 and XCL1, produced by natural killer (NK) cells, and CCL4, produced by tumor cells. In the TME, DCs are activated in response to danger-associated molecular patterns (DAMPs) and uptake tumor antigen uptakes. Subsequently, DCs migrate to lymph nodes (LNs), where they cross-present tumor antigens to T cells, activating tumor-specific CD8+ cytotoxic T cells (CTL). CTLs traffic back to the TME and kill tumor cells. However, tumors have evolved to escape immune responses through various mechanisms (right), including inhibition of DC recruitment, differentiation, survival, function, and exploiting the tolerogenic capacity of DCs. Tumor-derived β-catenin and prostaglandin E2 (PGE2 ) block DC infiltration by inhibiting chemokine secretion by tumor and NK cells, respectively. Vascular endothelial growth factor (VEGF) secreted by tumors downregulates NK cell-derived Flt3L, thereby inhibiting DC differentiation and survival. Tumors also impair sensing of DAMPs by DCs and DC migration into LNs. Tumors can also affect the cytokine secretion profile of DCs, polarizing them to a more tolerogenic state, leading to the accumulation of immunoregulatory cells, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and T regulatory cells (Tregs), in the TME, as well as the induction of checkpoint molecules and their ligand expressions, such as PD-1 on T cells and PD-L1 on tumor cells or myeloid cells.
Increased susceptibility to cancer in people with DC deficiencies, as well as aggravated tumorigenesis observed in Batf3 knockout mice, which lack cross-presenting cDC1s, demonstrate the importance of DCs in mediating antitumor immunity. The strong correlation between the abundance of tumor-infiltrating cDC1s and clinical outcome in cancer patients further corroborates these observations. Therefore, inhibition of cDC1s is beneficial for tumor progression.
Tumors have evolved to escape immune responses through various mechanisms, including abrogating DC function. Tumor cells establish a highly immunosuppressive TME that perturbs DC recruitment, differentiation, survival, function, and exploits the tolerogenic capacity of DCs (see Fig. 1). Tumor-derived factors can limit cDC1 recruitment to the tumor site by modulating DC-attractant chemokine production. For example, active β-catenin in tumors reduces CCL4 production. Similarly, prostaglandin E2 (PGE2 ) impairs CCL5 and XCL1 production by NK cells. Tumors can also inhibit cDC differentiation and survival through the downregulation of NK cell-derived Flt3L by secreting vascular endothelial growth fac tor (VEGF). Likewise, PGE2 can inhibit iDC differentiation, as well as cDC maturation and survival. Moreover, IL-6 in the TME, produced by both tumor and immune cells, also inhibits cDC and iDC differentiation. Tumors inhibit DC activation also by impairing sensing of DAMPs. For example, tumor-infiltrating cDCs upregulate TIM-3 expression, which interacts with an alarmin (HMGB1) and blocks nucleic acid recruitment into DC endosomes.CD47 expression by tumors also impedes tumor DNA sensing by cDCs. DC migration to LNs, a key step for the generation of antitumor T cell responses, also can be restrained by tumor-derived liver X receptor (LXRα) ligands. Another mechanism employed by tumors to bypass DC-mediated immunity is to alter their antigen profile. Tumors can post-translationally modify their antigens, such as MUC1 and HER2 glycosylation, and render DCs unable to process these antigens by blocking antigen transport from early endosomes to downstream compartments.
Tumors can also affect the cytokine secretion profile of DCs, polarizing them to a more tolerogenic state and perpetuating an immunosuppressive TME. For example, Versican, a tumor-derived TLR2 ligand, induces IL-10, IL-6, and their receptor expression in DCs. IL-6 can downregulate MHC-II and CCR7. IL-10 secretion, by DCs and macrophages within TME, can abolish IL-12 production by DCs. IL-6 and IL-10, among other TME factors such as VEGF, also trigger signal transducer and activator of transcription 3 (STAT3) signaling, which is hyperactivated in cancer and contribute to tumor growth and immunosuppression in TME. STAT3 signaling can upregulate the expression of immunoregulatory molecules in DCs, such as programmed cell death ligand 1 (PD-L1), which binds to the inhibitory receptor PD-1 on T cells. Moreover, STAT3 activation can inhibit DC maturation, as well as DC expression of MHC-II, co stimulatory molecules, and IL-12. STAT3 signaling also plays a key role in the accumulation of an immature myeloid cell population with immunosuppressive functions, so called myeloid-derived suppressor cells (MDSCs), at the TME. MDSCs mediate their immunosuppressive effects through a myriad of mechanisms, including the activities of arginase-1 (ARG-1) and inducible nitric oxide synthase (NOS2), as well as the secretion of immunoregulatory cytokines, such as IL-10 and TGF-β. In addition to directly inhibiting T cells, MDSCs can also impair the differentiation, maturation, and antigen presentation ability of DCs. For example, TGF-β can induce epigenetic modifications that impair DC function and differentiation.
Another immune escape mechanism utilized by tumors is skewing T cell differentiation. IL-10 and TGF-β induce Tregs, which inhibit effector CD8+ and CD4+ T cell functions. Tregs may also modulate cDC2 function and migration, leading to inhibition of cDC2 mediated proinflammatory Th1 differentiation of antitumoral CD4+ T cells. Additionally, tumors overexpress matrix metalloprotein ase-2 (MMP-2). MMP-2, through its binding to TLR2 on DCs, conditions DCs to produce low levels of IL-12 and to express OX40-L, thereby biasing antitumor CD4+ T cells toward Th2 differentiation associated with anti-inflammatory responses.
Finally, TME is highly hypoxic, deprived of adequate oxygen. One underlying mechanism for tumor-promoting effects of hypoxia is its contribution to immunosuppression, such as by inducing Tregs and MDSCs. Hypoxia also mediates metabolic reprogramming in immune cells, including DCs. Hypoxia enhances the production of adenosine and IDO by DCs, whose activities can inhibit T cells and NK cells. Hypoxia also causes ER stress, which can reduce DC maturation. Moreover, ER stress leads to abnormal lipid accumulation in DCs, which inhibits the translocation of peptide loaded MHC-I molecules to the cell surface, thereby blocking antigen cross-presentation.
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