Dendritic cells are usually inactive in state. But can be activated in some pathological conditions.
The role of dendritic cells in cancer is evolving. They are important mediators of adaptive immune response in cancer and also promote cancer growth via inducing immunotolerance. Their different subsets may have varying role in cancer microenvironment. A chunk of recent work has focused on dendritic cell activation vis-a-vis induction and upbolstering of immune responses against cancer or their use in anti-cancer vaccines, however, with limited success.
Sure! I can not recognize any tumor-derived stimuli, which could activate DC of the host. Also, I am not inclined to consider this question as central in tumor immunology. Irrespective of the state of dendritic cells and many other immunoregulatory components, we well know that allogeneic tumors almost always are rejected, whereas syngeneic tumors almost always kill recipient. Second state is well known "escape", which can be accompanied by a number of immunoregulatory effects mediated by tolerogenic dendritic cells, induction of myeloid suppressor cells, Tregs, etc. At present, many efforts are aimed on prevention of these immunoregulatory effects. This is important. However. I think, these effects are secondary to more important factors, such as deficiency in T cell repertoire and low immunogenicity of tumor cells. Then, instead of rejection we see tumor evolving under pressure of inefficient antitumor host immune response to be less immunogenic and more malignant. I think that improvement of repertoire by the way similar to passive immunization against tumor cells will be much more successful.
Clinical trials on DC therapy is ongoing as we speak at different phases with different levels of success. Therefore, we may have to wait to see and say they are useless. [By the way, precisely speaking, DC-vaccine would be most likely therapeutic]. Needless to say that the involvement and status of DCs are differ greatly during the progress of the cancer and are case-by-case with the patients. Perhaps we may have to narrow down the topic a bit would help discuss.
There are two separate issues at least in regard to this question. First would be is there any data suggesting that dendritic cells have a role to play endogenously in tumor growth. This is difficult as it is clear now that DCs can play both a pro-inflammatory role to initiate an adaptive immune response and a negative regulatory role in inhibiting that response. For instance our group and others have shown that the TAM receptors on DCs play a critical role in blocking induction of immunity mediated by tumor cell death. Thus, one could envision that blocking this pathway could in the future be important in assisting the generation of an adaptive immune response in patients with cancer. The second issue is whether there is a role for DC vaccination in tumor therapy. Currently there is one approved therapy that has some DC component (Provenge) as part of the treatment (Provenge is basically a PBMC isolation with addition of an proprietary antigen to this) and multiple other small biotech companies with studies in ovarian CA, breast and gastric CA and leukemia. Whether these studies will show some benefit is not known currently.
Talking about DC, definately they can be activated in different conditions, including infections and autoimmune diseases. The same is true for cancer - DC can be activated by malignant cells directly (especially dying tumor cells) and indirectly by the tumor stromal elements. This is why tumor immune surveilance saves us for a long time. DC can be suppressed, inactivated or polarized in the tumor environment.
Ansering other questions in other comments, DC are involved in tumor initiation as well, and it was shown that depleting DC might support tumor growth. One paper in Blood last year shows that DC might directly increase genomic instability and thus support tumor initiation.
Regarding Dc vaccines, they perfectly works in animal models since the whole process is quite fast. Not in humans, where chronic tumor growth causes a lot of other changes in many different systems. The solution seems to be in a combination therapy, where the tumor microenvironment should be first targeted, the immune system should be activated (second), and probably tumor antigen-specific immunotherapy applyed as a third step. Please do not forget that even psychological stress in cancer patients suppresses the development of antitumor immune response significantly. Animal studies directly showed that altering social lifestyle in mice markedly up-regulated efficacy of immunotherapy.
Excellent answer, Michael! One more question. How can DC discriminate between normal and malignant cells?
In my view, dendritic cells can not discriminate it directly. They can recognize stress as low pH present in the tumor microenviroinment and activate in this context. Than, they can present to T cell proteins that are superexpressed by tumor cels and those that are mutaded in these cells. So, CD8 T cells specific for those proteins would be able to kill the cells that superexpress that antigen or that have it mutated, eliminating, then, the malignant cells.
Evidently, this presumes active role of T lymphocytes and passive role of DC in tumor recognition and implyes their involvement into many other pathological conditions. This picture seems very different from the one in response of DC to microbial pathogens.
Mariana is quite right, and this means a direct ACTIVE role of DC since all Ags (including tumor Ags) should be presented to T cells in order to make then real effectors cells. Please also keep in mind, that innate immunity, which is not Ag-specific, is also quite important in tumor elimination. DC are also important for regulating NK, NKT, gammadeltaT and other cells (including macrophages, mast cells and neutrophils). All of them are significant in tumor surveilance. Thus, there is nothing more important than DC.
However, Dmitry is very right that the role of DC in anti-microbial and antitumor immunity is different.
Finally, please do not play a lot with terms "activation" and "suppression", since activation of immune cells might means activation of Tregs or MDSC, which eventually suppress immune responses. In addition, local and systemic immune responses might be quite opposite, as well...
It is hardly to call recognition of indefinite pathology as "active". However, Michael is right saying that DC make real effector T cells better, especially in primary responses. Different antigens can be presented by a great number of cellular types expressing MHC molecules. Recognition of peptides of mutant proteins in the context of MHC class I molecules seems the most important in antitumor responses. I should note also that memory T cells can obviate requirement in costimulatory signals of DC.
Several interesting answers are present which address the application of DCs in tumor immunotherapy. I think it would be worthy to isolate a part of solid tumor from the body of cancer bearning patient through biopsy, then digest this tissue by mechanical or physicochemical digestion (Freez and thaw, Ultra sound and enzymatic approach) of course in steril condition or by filtering the resulted material through 0.22 micrometter filter. In next step puls the PBMC isolated DCs to this resulted antigens in in vitro cultur and after DC maturation, transplant these hyperactive DCs to the patients body near the tumor site. In this way we can bypass the tumor microenvironment which can make the naive DCs anergic to tumor cells by secreting TGF-B for instance. Has anybody had this experience so far?
The answer is probably yes. In virus induced tumors, like cervix carcinoma, virus specific
antibodies can persist after tumor invasion (malignant phenotype). For future research you can do a closer look for the persistence of virus specific IgA antibodies.
There are important topics inside this discussion and I can also include another one. The term "DCs" are so much vast to put in one unique package. We have (at least in humans) plasmocytoid DCs, myeloid BDCA1+ and mDC BDCA3+, inflammatory DCs and others... those cells could be activated by different kinds of ligands (endogenous or exogenous) and when we go to mouse models we can find papers describing one or other DC-type as the most important for each work. Still, If we start to compare different types of cancer, for example, breast cancer x colorrectal cancer; lung cancer x melanoma...we also find diverse roles by different DC subtypes! Good question!
Dear Mohammad, this scientific field has more than 15 years history. A great number of scientists do this now with restricted success. For example, in melanoma patients injections of pulsed DCs frequently cause DTH-like inflammations. There are individual cases of stabilization of disease. You should take into account, that suggested principle of pulsing will result in responses of mainly CD4 T cells, but not CD8 CTLs. To get success in induction of CTLs, you should make DCs with endogenously expressed tumor antigens.
Answer to Mohammad. This schedule was done many times and used in clinical trials. The only concern is why to inject DC vaccine next to tumor mass. If DC are already pulsed with a mixture of tumor antigens and can present them to both CD4 and CD8 T cells, they need to be in lympho nodes. There are a few trials where pulsed DC are injected directly into the lyph nodes and induction of CTL is great. However, one still needs to deal with both local and systemic tumor-induced immunosuppression. Now DC vaccines are rationally combined with low dose chemotherapy or radiation therapy to alter the tumor microenvironment. But this is a different story.
Answering to Rodrigo. This is very right. We also need to keep in mind that different cancers employ different way and factors to alter DC: from inducing their apoptosis (common for melanoma), to polarizing DC to regDC (i.e., lung carcinoma) to suppressing DC function (common for prostate cancer).
Please check details about Dendritic cell therapy a technology being studied for treatment of cancer
Is it not possible to develop mechanisms for maturation of dendritic cells in cancer patients (which often does not happen and could be one among the reasons for tumor cells not be chewed up by dendritic cells) itself rather than get it done otherwise and then to inject DC vaccine?
I think, any therapy should be aimed to clearly determined targets. Unfortunately, the approach is targeted to stimulate immune system nonspecifically and does not solve central problem. Tumor is result of evolution of malignant cells under pressure of immune surveillance. The presence of tumor means that one has obviated immune surveillance and does not contain real (mutant) tumor-specific antigens capable to induce efficient immune response. In this context DC therapy may be successful in immunodeficient patients having primarily insufficient immune function. It would be expected that this deficiency served tumor cells expressing real tumor-specific antigens and made possible to induce immune response by DC. Patients with primarily normal immune function unlikely will get benefits of this therapy, because possible targets are already rejected by their own immune system, whereas remaining have passed evolution to be low immunogenic. At the same time, risks to obtain autoimmune diseases will be increased. Tumor associated (non mutant) antigens would be relevant targets, but many of them are expressed in medullary thymic epithelial cells and own T cell repertoire of patient is selected not to respond on these antigens efficiently. As result, immune system contains only low avidity clones, specific to self tumor-associated antigens. Evidently, nonspecific stimulation of them will result in inefficient immune responses and downregulatory effects. However, high avidity clones specific to tumor associated antigens of patient may be found in T cell repertoire of allogeneic donor. Genes encoding their TCRs may be cloned for subsequent transduction of T lymphocytes of patient. This approach is similar to well known passive immunization with antibodies.
My view on this was the understanding that inspite of the presence of tumor specific antigens dendritic cells since they do not mature in cancer patients are not able to recognize and bind those specific antigens and so a stimulation for maturation of immature dendritic cells with enhanced capability to identify tumors
A further enhancement of DC´s in virally induced tumors could be possibly achieved with bacterial Superantigens from the relevant anatomical region. Example: Chlamydia trachomatis in Cervical carcinoma.
Dear Mr. Lei Lui, I am interested about the paper you have refered, but I can't have its access, can you please help me to get it.
Thank you.
We need to know the initiator phase to elucidate the role of dendritic cells in cancer. Once we come up with the triggering factors that induce carcinogenesis, we will then be able to dissect out mechanisms of non-recognition of cancer cells by lymphocytes. Tumor micro-environment or the niche stromal cells may be responsible for the growth of suppressor Treg via dendritic cell-induced chemical release. We see TGF-beta upregulation in tumor niche that may activate Treg and suppress adaptive immune responses. A clear understanding on the role of innate immune system in cancer may determine the mechanism that shape the adaptive immunity.
Dear Syed, let me assume that adaptive immunity can be first. T cell repertoire contains significant percent of activated T cells capable to migrate via non-lymphoid tissues. It is evident now, that many of them are not experienced by external antigens, because may be found even in gnotobiotic animals. Some of them may be effector CTLs capable to destroy tumor cells immediately and would represent main cell type performing the function of immunological surveillance. Second step would consist of activation of innate immunity for subsequent promotion and enhancement of adaptive response. I think that this sequence of events really takes place in response to allogeneic tumors. Anyway, innate immune responses to allogeneic tumor cells that I could observe, were dependent on CD8+ cells. It may be, similar order of events would be beneficial in real antitumor responses.
Supporting information for this statement you can find here
https://www.researchgate.net/publication/6170036_The_functional_role_of_spleen_neutrophil-like_cells_in_the_immune_response_to_allogeneic_tumor_cells?ev=prf_pub
and here
https://www.researchgate.net/publication/216544249_Accumulation_of_neutrophils_in_the_spleen_of_mice_immunized_with_cells_of_allogenic_tumors?ev=prf_pub
Article The functional role of spleen neutrophil-like cells in the i...
Article Accumulation of Neutrophils in the Spleen of Mice Immunized ...
As I said earlier that innate activation is a key regulatory mechanism to shape adaptive immunity needs to explore in more depth. As for example, we get viral infections that activate innate system including neutrophils and B cells, later comes adaptive system. Both systems get activated in lymphoid tissues where exchange of information occurs to bring high affinity antibody maturation as well as both CD8 and CD4 maturation. If cancer cells induce neo-antigen, we probably assume that CD8 activity will be generated with profound NK-T cells activation. These responses will be via MHC restrictions. Since self-antigen undergo thymic selection processes, cancer cells are not eliminated, only a part of cells will be eliminated those express neo-antigen, which are not self. However, a lot to know how cancer cells evade lymphocyte-mediated killing.
Dear Syed, I should note that my experience deal with responses to allogeneic tumor and normal cells. In contrast to responses to viral antigens, these responses can be (and really are, in general) MHC-unrestricted, because foreign MHC molecules can be recognized directly by TCRs. Certainly, these responses should be considered only as a model for real antitumor response, but I think that exploring of these models can result in useful knowledge allowing to operate by antitumor responses. I should note that in my parctice, I never seen any increase in NK1.1 positive cells during immune response to allogeneic tumors. Moreover, ablation of NK1.1 positive cells slightly up-regulated the responses and resulted to more efficient cloning of CD8+ T cells. Responses to viral infections may at some extent differ from transplantational and antitumor responses by the presence of TLRs, which could directly activate innate immunity. The mechanism of this activation in antitumor and transplantational response stays elusive. Therefore, I suggest seditious idea that DC can be altogether (or in general) unrelated to antitumor and transplantational immunity. Certainly, we should study innate immunity as a key regulatory mechanism capable to shape adaptive immune responses. However, we should not be carried away by this idea also.
Dear, Dmitry, yes I do agree with you completely. The scenario is more complicated than we imagine as they are not only context-dependent but also to concentration or overload dependent. My expertise is understanding of tolerance mechanisms and signal transduction in human autoimmune disease. I am more interested in identifying triggering factors, which I believe that they are widely distributed in our microbiome paradigm. They get activated once the cell defense (epithelial) system is compromised and in long run a tolerance defect may arise which may lead to either cancer transformation and/or autoimmunity. The key role players would be macrophage for cancer and dendritic cells for autoimmunity.
This is very interesting field! And thank you very much for very interesting answer! I should note that there are two subsequent questionable dilemmas. First is arising of mostly epithelial tumors in human and mesenchymal tumors in mice. In the context of microbiome paradigm It would be nice to see common explanation for different organisms. Second is apparently close association of autoimmunity with lymphomas, but not epithelial cancers. How do you see the role of macrophages in cancer transformation?
Thanks, Dmitry, yes, macrophage play a vital role as it depends on polarization. M1, M2 and some overlaps, they are mostly cytokine dependent. M2 promotes cancer whereas M1 induces anti-cancer immunity. Here are some examples of M2 and fibroblast contributing to cancer formation.
Thank you very much, Syed. I do agree that this really works, when CD8 T cell response is compromized. Thank you!
Dear friends, there is an emerging novel approach of activating specific anti-tumor dendritic cell response through the use of oncolytic viruses such as NDV, measles, vesicular stomatitis and reo viruses
Dear Naresh Kumar Sood, did you read full discussion? Please, be accurate with terms! As it was noted above, dendritic cells can not respond to tumor specifically. So, "specific anti-tumor dendritic cell response" seems senseless. It may be, you say about oncolytic viruses as adjuvants capable to promote antigen-presenting function of DC and induction of specific adaptive responses to tumor cells? Again, as it was noted above, irrespective of DC function, there is big problem to identify tumor antigens, capable to induce efficient immune response.
Certainly, we still have opportunity to solve this problem by broadening and correction of T cell repertoire. I think, these tasks are central to immunotherapy of tumors and need to develop relevant approaches in near future.
Hi Guys:
Interesting discussion. To understand what a tumor environment looks like during progressive tumor growth, or tumor rejection, I have attached a paper, "Macrophage Arginine Metabolism and the Inhibition or Stimulation of Cancer. This paper defined biochemically that macrophages promote tumor growth by producing Ornithine (via Arginase) and other growth factors. And, tumors are rejected by macrophages producing Nitric Oxide, and amplifying other killer responses. Both activities result from the enzymatic cleavage of Arginine in slightly different ways, a dual metabolic pathway only macrophages possess. This paper is the origin of both the idea that macrophages can either promote or inhibit cancer, and why subsequent experiments caused me to name these 2 different activities, M1 and M2. I agree with the discussants that it is very difficult to find epitopes on human cancers that are recognized by T cells. So, I would put my effort into stimulating M1s from M2 like macrophages. If there are T cell epitopes, it will still be necessary to stimulate M1 activity because M1 directs T cells to make a Th1/cellular killer response. Innate First: Adaptive Second. That is why I renamed macrophages M1 and M2 to highlight that macs activate T cells - not vice versa. After this, T cells further activate M1 (or M2) depending on whether M1 or M2 was dominant to begin with. A fundamentally different way of understanding how immune responses work. See Mills M1/M2 JI 2000. Good luck, Charlie
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