Strategies and challenges in eliciting immunity to melanoma

Ferguson, Andrew R.; Nichols, Lisa A.; Zarling, Angela L.; Thompson, Elizabeth D.; Brinkman, C. Colin; Hargadon, Kristian M.; Bullock, Timothy N. J.; Engelhard, Víctor H.

doi:10.1111/j.1600-065x.2008.00620.x

Cited by 20 publications

(17 citation statements)

References 122 publications

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“…In concert with primary tumors, our study identifies immune suppressive molecules in tumor-draining LNs, suggesting that immune mechanisms operating in metastatic LNs 25 , 37 , 61 , 62 may at least in part be similar to those in primary tumors. 63 In contrast to primary tumors, we found a significant correlation between LECs and FoxP3 + lymphocytes.…”

Section: Discussionmentioning

confidence: 75%

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

et al. 2018

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Increased density of tumor-associated lymphatic vessels correlates with poor patient survival in melanoma and other cancers, yet lymphatic drainage is essential for initiating an immune response. Here we asked whether and how lymphatic vessel density (LVD) correlates with immune cell infiltration in primary tumors and lymph nodes (LNs) from patients with cutaneous melanoma. Using immunohistochemistry and quantitative image analysis, we found significant positive correlations between LVD and CD8+ T cell infiltration as well as expression of the immunosuppressive molecules inducible nitric oxide synthase (iNOS) and 2,3-dioxygénase (IDO). Interestingly, similar associations were seen in tumor-free LNs adjacent to metastatic ones, indicating loco-regional effects of tumors. Our data suggest that lymphatic vessels play multiple roles at tumor sites and LNs, promoting both T cell infiltration and adaptive immunosuppressive mechanisms. Lymph vessel associated T cell infiltration may increase immunotherapy success rates provided that the treatment overcomes adaptive immune resistance.

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Section: Discussionmentioning

confidence: 75%

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

et al. 2018

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“…In vivo administration of nanoparticles carrying immunostimulatory miRNA converts endogenous immunosuppressive DC into cells capable of activating robust anti-tumor responses that inhibit progression of established ovarian cancers (150). Moreover, supplementation of stimulatory cytokines whose expression is often suppressed in tumor-associated DC, such as IL-12 and IFNα, can enhance T cell effector function elicited by endogenous DC (151, 152). Significant efforts have also been made to optimize exogenous DC-based cancer immunotherapies.…”

Section: Immunotherapeutic Strategies For Interfering With Tumor-assomentioning

confidence: 99%

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Hargadon¹

2013

Front. Immunol.

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Dendritic cells (DC) are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programing of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor immunity.

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“…It is therefore very likely that differences in these or other soluble factors derived from B16 melanoma variants account for the different effects of melanoma-derived factors on DC maturation and activation observed in our current and previous studies and the study by Alshamsan et al (2010). Based on earlier studies that document the B16-F1-associated dysfunction of tumor Ag-specific CD8 + T cells (Hargadon et al, 2006;Ferguson et al, 2008) and our current observations that B16-F1-derived factors suppress the maturation and activation of DC2.4 and JAWSII cells, it will be interesting to determine whether these B16-F1-altered DC lines induce the type of incomplete CD8 + T cell differentiation associated with this tumor in vivo. We believe that this in vitro model offers a nice system for investigating the impact of tumor-altered DC on the quality of anti-tumor immune responses and we are currently exploring how these tumor-altered DC influence both CD8 + cytotoxic and CD4 + helper T cell activation and differentiation.…”

Section: Discussionmentioning

confidence: 78%

“…The basis for this melanoma antigen-specific CD8 + T cell dysfunction in both patients and animals has remained unclear. While it is possible that tumors or tumor-derived factors directly suppress effector CD8 + T cell differentiation, it has been suggested that this T cell dysfunction might also arise from an influence of the tumor on cross-presenting DC (Hargadon et al, 2006;Ferguson et al, 2008). This latter possibility has been difficult to address by either in vivo or ex vivo analyses due to the limiting number of DC that can be isolated from melanoma patients or tumor-bearing animals.…”

Section: Discussionmentioning

confidence: 99%

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

Hargadon

Ararso

Forrest

et al. 2012

American Journal of Immunology

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Dendritic cells function as potent regulators of both innate and adaptive immunity to tumors and the regulatory activities of these cells are tightly linked to their maturation and activation status. Despite the critical role played by dendritic cells in the induction of anti-tumor immune responses, the number of dendritic cells that can be isolated from experimental animals is limiting and often precludes in-depth analyses of these cells. To overcome this limitation, dendritic cell lines have been established and have facilitated the experimental study of dendritic cell biology. In this study we compare the dendritic cell lines DC2.4 and JAWSII as in vitro model systems for studying the influence of melanoma-derived factors on dendritic cell maturation and activation. Using flow cytometry and ELISA analyses, we evaluate the expression of costimulatory/MHC class II molecules and proinflammatory cytokines/chemokines by these dendritic cell lines in their resting state and following LPS stimulation in the presence or absence of B16-F1 melanoma-derived factors. Results: We demonstrate that soluble B16-F1-derived factors suppress the LPSinduced upregulation of CD40, CD80, CD86 and MHC class II on both the DC2.4 and JAWSII dendritic cell lines. Interestingly, LPS-induced secretion by DC2.4 cells of the proinflammatory cytokines/chemokines TNF-α, IP-10, MIP-1α, MIP-1β and MCP-1 is also altered by B16-F1-derived factors, whereas JAWSII cell cytokine/chemokine production is affected to a lesser extent by such factors, with only IL-1β and IP-10 production being suppressed. Conclusions/Recommendations: We conclude that melanoma-derived factors can suppress dendritic cell maturation/activation and that the DC2.4 and JAWSII dendritic cell lines are effective in vitro models for future studies that aim to (1) identify factors that influence both the susceptibility and the resistance of dendritic cells to tumor-mediated immunosuppression and (2) investigate the influence of tumor-altered dendritic cells on the quality of anti-tumor T cell responses.

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Strategies and challenges in eliciting immunity to melanoma

Cited by 20 publications

References 122 publications

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

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Strategies and challenges in eliciting immunity to melanoma

Cited by 20 publications

References 122 publications

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Melanoma-Associated Suppression of the Dendritic Cell Lines DC2.4 and Jawsii

Contact Info

Product

Resources

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Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma

Lymphatic vessel density is associated with CD8⁺ T cell infiltration and immunosuppressive factors in human melanoma