ImmunotherapyVol. 5, No. 2 EditorialFree AccessAre dysfunctional monocyte-derived dendritic cells in cancer an explanation for cancer vaccine failures?José Alexandre Marzagão BarbutoJosé Alexandre Marzagão BarbutoUniversity of São Paulo, Institute of Biomedical Sciences, Department of Immunology, Laboratory of Tumor Immunology, São Paulo, SP, Brazil. Search for more papers by this authorEmail the corresponding author at jbarbuto@icb.usp.brPublished Online:15 Feb 2013https://doi.org/10.2217/imt.12.153AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: cancer immunotherapycancer vaccinesdendritic cellsmonocyte-derived dendritic cellsImmunotherapy of cancer has been an elusive, though long-sought target. The unique properties of the immune system indicate that, if it could be directed against cancer, it should be able to eliminate it from the body. This hypothetical scenario is reinforced by the occasional spontaneous or sometimes, therapeutically induced, rejection of malignant tumors by a patient’s immune response [1].However, from the conceptualization and observation of this possibility to the design of effective immunotherapeutic approaches against cancer lies a long road not yet mapped. Among the many possible tools that could redirect the immune system, dendritic cells (DCs), with their ability to connect innate and adaptive immune responses, appear to be crucial players [2]. Through their innate ability to recognize tissue homeostatic imbalances, these cells undergo a maturation process, which, in turn, allows them to activate naive T lymphocytes and start adaptive immune responses against antigens they captured and presented to the T cells [3]. As a counterpart to this ‘effector’ pathway, DCs also play an essential role in the maintenance of health by preventing destructive autoimmune responses. If there is no detectable homeostatic disequilibrium in a tissue, DCs within it still present the captured antigens to T lymphocytes, but in such a way that, instead of inducing the activation of immune responses directed to the elimination of the antigen, they induce responses that lead to the ‘acceptance’ of the antigen and, therefore, immunologic tolerance.Such a tolerogenic role of DCs unravels the puzzling observation that immunocompetent individuals fail to recognize and mount effector responses against tumor antigens, which would, under other circumstances, induce such responses. This is explained by the fact that DCs within tumors do not react to tumors as a diseased tissue and consequently remain immature [4], thus inducing tolerance to the tumor. With such equilibrium established between the tumor and the immune system, tumors are ‘allowed’ to grow unchecked by a perfectly functional immune system, which would otherwise reject them.The realization of the role DCs play in this context was not only a significant step towards better understanding of the tumor–immune system complex interactions, but also opened exciting new possibilities for intervention. If failed DC activation and consequently failure of tumor antigen presentation is a factor that contributes to the tumor escape from the immune system, then the presentation of tumor antigens by mature DCs should be able to engage the immune system effectively against cancer.When it became possible to generate DCs in large enough quantities for clinical use in vitro and to induce these DCs to mature [5], immunotherapeutic approaches using these cells loaded with tumor antigens were quickly designed and tested. It became clear that various parameters of the immune response were affected in patients submitted to DC vaccination, showing that these cells were able to present the loaded antigens to the patients’ immune system [6]. Furthermore, clinical responses were obtained [7,8], further confirming the potential of these strategies. Nonetheless, these responses were not as prevalent and definitive as the rationale behind it would predict and lagged below the initial expectations. This apparent failure could have dire interpretations. Could it mean that effective immunotherapy of cancer through the induction of an active immune response in the patient is not really possible [9]? Or, at least, that DCs are not the right tool for the job? Although this would be a hasty interpretation, it was a tempting one. Additionally, faced with the apparent overall failure of the many different approaches tried over the years to harness the immune system to fight cancer, one could even be lured to accept that, actually, immunotherapy of cancer as a general approach is not a realistic tactic in the management of the disease. However, this negative outlook would be mistaken. Truly, when one looks to the many immunotherapeutic approaches to cancer, it is possible to recognize a sequential pattern of discovery, enthusiasm and, often, disappointment. However, when the disappointment has been followed by persistent investigation, it has resulted in the effectiveness of that specific approach being shown. For example, this is the case of the monoclonal antibodies that were initially regarded as ‘magic bullets’, later named ‘misguided missiles’, but are now drugs of choice in some clinical settings [10].It is true that no immunotherapeutic approach has yet reached the fullness of its initial promises; however, it must also be acknowledged that the intricate interactions within the immune system and of the system with the neoplastic tissue are only recently beginning to be considered in their real complexity. Even today, this complexity is often forgotten in the debate around the role of immunotherapy in cancer.This can be noted, for example, in the emphasis put on the search for CD8+ T-cell responses against tumor cells. These cells are seen as ‘ideal’ effectors of antitumor immunity, as they recognize antigens in the context of MHC class I molecules, which are present in all nucleated cells. Furthermore, they are cytotoxic and therefore able to directly kill tumor cells. However, tumor cells do not always present MHC class I molecules and it is possible that the direct cytotoxicity against the tumor is not the most relevant function of effective antitumor CD8+ T cells, but rather their ability to secrete cytokines when challenged with the tumor [11]. Moreover, even the ‘undisputed’ cytotoxic function of CD8+ T lymphocytes can be debated. This function has been extensively demonstrated in viral infections in animal models, where the T cells’ ability to kill infected cells has been considered and demonstrated to be an essential component of antiviral immunity. In humans, however, the congenital absence of CD8+ T cells is, surprisingly, not associated with susceptibility to viral infections, but with pulmonary bacterial infections [12]]. These controversial points are rarely mentioned in the rationale of immunotherapeutic schemes, but might, if considered, shed light on unexpected results sometimes obtained.Another oversimplification appears in the consideration of DCs’ role in immunotherapy. If the rationale behind the use of these cells is correct, and this would be hard to deny considering their known role in the immune system as we understand it today, then the oversimplified view of the relative failure of DC-based schemes would be that active immunotherapy in cancer is not effective.Yet, there are DCs and DCs. That is, the term ‘dendritic cell’ has been applied to cells that, although related, display very different functional properties [13]. Despite this diversity, most clinical studies are based on the use of monocyte-derived DCs (Mo-DCs). These are easy to generate in vitro, can be loaded with tumor antigens by various strategies and can be activated by a series of maturation signals. Although not consistent, many clinical responses have been achieved with such approaches and it is therefore impossible to deny that Mo-DCs used in antitumor vaccination protocols are able to modify the natural history of the disease. Why then is there inconsistency in the results? Why is it not common to obtain complete remissions in DC-treated patients?It has been known for quite a while that DCs within tumors are negatively influenced by their microenvironment and do not show the expected mature phenotype. This is one of the many reasons why the use of monocytes as DC precursors has been so attractive. These peripheral blood cells are not only easy to obtain, but if differentiated in vitro away from the negative influences of the neoplasia should become functional DCs, unaffected by the tumor. However, as recently shown in breast cancer patients, this is not the case [14]. Mo-DCs from these cancer patients are actually functionally biased and induce, at least in vitro, powerful Tregs. If this happens in other patients, then the apparent failures of DC vaccination could be ascribed to this functional bias. Therefore, it would not be surprising that these less-than-optimal DCs, biased to the induction of regulatory responses, are unable to break the state of tumor tolerance in patients. This could never be interpreted as an absolute inability of DCs to induce effective antitumor responses. Actually, what one should urgently seek is the means to bypass this functional deviation and obtain mature and functionally effective Mo-DCs from cancer patients, thus achieving the expected functional response of the patients’ immune system.Therefore, as for any attempt to understand nature, but more crucially in the translation of basic knowledge to clinical practice, it is important to consider all data. If this does not happen in our field, well-designed strategies can be put together, but they may miss the target, not because immunotherapy of cancer is ineffective, but because the wrong path to it was chosen.AcknowledgementsThe author thanks Patrícia C Bergami-Santos for her critical reading of the manuscript.Financial & competing interests disclosureThe author thanks FAPESP (Sao Paulo, Brazil) and CNPq (Brasilia, Brazil) for the financial support of his work. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Dall ’Oglio M, Srougi M, Barbuto JA. Complete response of metastatic renal cancer with dendritic cell vaccine. Int. Braz. J. Urol.29(6),517–519 (2003).Crossref, Medline, Google Scholar2 Steinman RM. 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The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download