Cancer Of The Spleen

>> good afternoon. it is my great pleasure and delight to introduce today's wednesday afternoon lecture speaker, dr. xuetao cao, the president of the chinese academy of medical sciences, and of the neighboring peking union medical college in beijing, china.

dr. coup cao is one of the top immunologists in china with a top career, at age 28 the youngest to earn the title of medical professor in china, by age 40 was named vice president of the prestigious second military medical university in shanghai, where he learned his

m.d. and ph.d. his laboratory focuses on the understanding of innate signaling and immunity in inflammation, identification of cell subsets and new molecules and dendritic response and cancer immunotherapy, a subject of importance and topicality.

his group identified more than mediators and regulate regularrors and characterized subsets with function in immunity, regulation and cancer which you'll hear about today. he's published more than 220 original papers, as corresponding author, numerous

top tier journals. serves on the editorial or advisory board of a number of journals "cell," science and translational medicine, as a scientific administrator dr. cao has tasked to restructure the chinese academy, most akin to the nih, research hospital and

laboratories, serves as one of the major focuses of academic research in china. this daunting task involves not simplying copying a western model but creating something novel that can work at a chinese federal level and enable the youngest generation of

scientists, basic and clinical, to flourish in their home country while embracing international collaborations. his honors include "nature" awards and mentorship for science, membership in the american association of immunologists, membership in the

chinese academy of engineering, german academy of sciences, french academy of medicine. dr. cao is a thought leader in cross-disciplinary research and worked for international collaboration and to enhance the global visibility of china's own research and development.

we're really thrilled to have him speaking with us today. please join me in welcoming dr. cao. [applause] >> thank you for the kind introduction. good afternoon, ladies and gentlemen.

it's a great honor to be here. first i want to thank the kind invitation to give me the chance to share the data from my laboratory in cancer and the immunity. i attended the intramural symposium the day before yesterday, attended a lecture,

which reminded me a lot of memorable things i had with bill, visiting china. i want to take this opportunity to express my thanks for his generous support to immunological society, and to me, in the last years. and also i have so many very

close friends in nih, so i'd like to take this opportunity to thank you for help also in my career. today i want to talk about the innate molecule, information of cancer. as we know, the immunity of the cancer becomes more popular,

also immunotherapy has been successfully applied in clinic. for example, the check point blockade and car t cell transfer. however, the clinical outcome is still limited. so, how to improve the therapeutic efficacy and how to

figure out what's the population of the cancer patient responsive to the cancer immunotherapy, the issue to our immunologists which need us to better understand most of the interactions of tumor and host what's happening in in vivo. many there are so many

mechanisms to affect the therapy and help cancer cell escape immunologic attack. there are things we should follow. as we know, the fundamental function of the immune system is to discriminate the cell and dangerous non-cell.

as we know, the immune cells are responsive, so they can be activated. in the last two decades we made much attention how to activate the immune response against we have identified many kind of activators, factors of immune system.

we understand the immune system can develop the regulation strategy to control the activation of their systems by upregulating regulator of immune suppressive cells in vivo. so how to activate immune response not only activate but also can find the way to

suppress. so the checkpoint blockadeleads to activation of immune response. so this is the balance of the immune system. how we can get the function or indications from the knowledge is also the good question we

should answer. the role in the initiation of immune response but also critical in the immune hemo stasis. how they can efficiently initiate the nature innate response against the pathogens, because the prr on the surface

which can (indiscernible) the self -- distinguish the cell and non-cell path. when the invading pathogens, the downstream pathways of the prr can be activated, chemokines, cytokines, interact with t cells and b-cells, so forming the immunological network to

eliminate signaling pathway, initiated and how this single pathway can be timely determined, it's the proper label, to avoid the o activation and prevent the harmful immunopathology is also a good question we immunologists should answer.

in the last two decades, my laboratory focused on new biology, dendritic cells, macrophage, how they can be what's the single pathway inside to it be regulated at the cellular level and immune response, inflammatory response can be initiated.

also we're very curious how the inflammation can be resolved. so we cellular molecule mechanics, resolving inflammation, especially at the (indiscernible) cell level and interested in the interaction of cancer cell and immune system, by upregulating the t regulators

or reducing the activation of the immune response. also, how about the immune system indicated by the primary tumors to create the favorable environment for circulating tumor cell colorization for the future metastasis in the distant organ.

we also are interested in this. also we're trying to translate the passing knowledge to the clinic, trying to set up the new approach to the cancer immunotherapy, or identify the biomarkers to predicate the prognosis of cancer patient, especially receiving the certain

kind of cancer immunotherapy. so why we ask the question today, i'd like to share data about the role of the innate sensor, two important sensors, in cancer progression and immunotherapy. i have several slides to briefly introduce the background why we

ask this question. so now there's a widely accepted concept in the tumor immunology is immunogenic chemotherapy. the chemical address can increase immunogeneticy, this is the new concept. now, 20 years ago, this is -- i had the first original paper

published in western countries. that's about which describes the combined use with adaptive chemo immunotherapy, also how the therapeutic in the tumor modal hepatocellular carcinoma has the highest incidence of mortality in china. so this study inspired me to

think about what's the chemical address can model the immunogenicity of cancer cell. and it is possible for me to find the new activating molecule or adjuvant molecule to activate dendritic cell or other cells which can be used for adaptive chance or vaccination, so we

contracted human cdna library, large scale automatic at that time, identified several null molecules including one hsp701, on the dendritic cell activation and antigen capacity, we find this is the neoadjuvant, combined to the receptor on the surface of dendritic cell and

activates or increases antigen preceding capacity of dendritic cell to active t cell response, tailing the tumor cell. and then how about shock, treating of the tumor cell, then we analyze the immunogenicity of tumor cell after the shock, also we find they can release the

official proteins and also have high expression of protein intracellularly. histoprotein can increase expression, so having the antigenic or immunogenic complex at the time, we used this complex to pass the dendritic cells and use the dendritic

cells to activate the tumor, we found increase the ctr response can be achieved. this we mind us, we can find the ways of identified adjuvant to activate anti-tumor immunoresponse. so this is the -- then we started to do clinical trial.

this clinical trial was headed by me, at the beginning. so we call this dendritic cell based immunotherapy, the vaccination, also chemotherapy low dosage, you can see here we can isolate monocytes, repair the dendritic cell, and then we let the patient receive the

chemotherapy for five days. then we have two rounds. dendritic cell vaccination. so from here you can see if the patient just received the chemotherapy, we have the limited opportunity response, however if we use the combined therapy of the chemo

immunotherapy, the objective response increased went up. this dendritic cell we prepared with the heat stress autotumor cell lysates, so this is just showing you the histoprotein or histotreatment can increase the tumor genicity of the -- tumor lysates of tumor cells, den

dendritic cell and identify what's happens to the patients after vaccination. you can see increased specific ctr response essentially coming to secreting t cell and reduction of immunosuppressive cytokines in the blood of the cancer patient after receiving

the dendritic cell chemotherapy. for example, decreased presence of il-10 and tgfb in the blood, and also we wondering what's the biomarkers can select or discriminate the part of the patients which are responsive to the dendritic cell-based chemo immunotherapy, with dozens of

biomarkers, the examples, finally we find went back to a study. so there is an expression of hsp70 positive tumor cell and cd4 50 in the tumor microenvironment patients will be responsive to dendritic cell this gives us another function

of clues. there is potent immunosuppression as the later stage of cancer patients so we analyzed immune suppressive cells in tumor mouse in cancer patient we identified several times of cells including 3 dendritic cells, how we

identified this population of the the mature cell can present antigen for t cells and activate t cell response. then one question arise, what's the (indiscernible) after t cell activation, so it's generally accepted because they are the (indiscernible) cell.

however, when we co-culture mature cell with stroma cells can go further and different shade to another type of dendritic cells with regulatory function can think back, inhibit t cell proliferation producing large amounts of nitric oxide. we identified this population of

cell in the tumor tissues. so this is the best study of the dendrite cell in tumor immunology. so what we learned from the clinical and passing study of dendritic cell based cancer cell-based therapy, improve the efficacy of the dendritic cell

vaccination, how to do it? and we tho identify biomarkers to predicate the patients who are responsive to the therapy, and also suppressing the suppressor, blocking the immune suppression of inflammation, benefit for cancer patients. this is to do for the research

in several respects. we should identify what's the innate signals in immunity, which can be utilized to design a new type of adjuvant for cancer immunotherapy. and also what kind of immune suppressive substance or molecule in tumor

microenvironment and even in the secondary organs of tumor-bearing host which can be deleted to benefit the cancer patients. and so we tried to identify the immunosuppressive or inflammatory factors in cancer, also used by biomarker of cancer

this is the back ground to the innate response inflammation response in cancer. there are several pathways for innate response. the tlr signaling and rig-1, so we identified several kinds of molecules on the cell surface or intracellular which can regulate

the pr signaling in the macrophage or dendritic cell through different mechanics. for example, the signal t independently the 10, the homolog from the human dendritic cell, we found this molecule on the surface can upregulate and recruit to promote rig-i and

disrupt the interferon production, so preventing the old activation of the immune response, inflammation. also coding rna because lsm3b i have several slides to show you later, we also moved our attention to the nuclei of the macrophage of the dendritic

cell, so we identified several epigenetic modifiers which played a role in cytokine production. for example, the tet2 cytokine production must be produced, must be initiated timely but if it continues to present so long a time it will induce the

harmful immune pathology, so one question to us, how to timely terminate the inflammatory cytokine production, later stage of innate response, especially the immune response, immune system has already eliminated the irradium pathways, for example control of the

interferon and how to terminate production of il-6, pro inflammatory cytokines. we analyzed the profile of the macrophage of dendritic cells, we find there are so many molecules upregulated, among them tet2 which can be upregulated, you can see here.

we're analyzed the tet2 macrophages and dendritic cells. what's their response? when we started to analyze the il-6 production there was no dramatic change. when we extended that, analyzed time cost until to 12 hours, there was dramatic difference of

the il-6 prosecution, especially tet2 deficiency where it has the il-6 production at later stage of innate response so this reminds us the tet2 may be the inactive regulator of the il-6 production, at the later stage of immune response and inflammation.

it's the terminator of the inflammation, or have to resolve the inflammation. this is just one key. now we understand the immune system can interact with environmental factors, and also can be modulated by the intrinsic factors including

metabolic molecules and epigenetic modifiers. so we can understand how the immune system is balanced by interaction with the environmental factors. so through this way we can enhance the enhancer, and suppress the suppressor, to be

(indiscernible) which also regulates the regulators for the control of organ rejection so this is all the -- i'll acknowledge about the immune regulation or balance the network of the immune system. so what we have done in immunobiology of apc and

interaction with cancer cell and what's the inflammation initiated by them in cancer progression and cancer immunotherapy, so we ask the question, what's the role of the innate sensors in host and cancer interaction especially at the level of the stroma and apc

and molecules. so i want to share two stories about the two molecules, rig-1 and recep-3. the role of the rig-i in the immune response, there are so many post-translational multiplications of innate sensors, you can see this is the

signaling responsible for the production of the cytokines, this is the rig-i, stain pathways for the activation of il-3, leading to the production of interferon, so we identify several molecules, just now i mention the siglac 3 and 122 responsible for post

modification of il-1. now the epigenetic regulators, by meta analysis of rig-i initiated interferon production, and then moved to the how we can identify epigenetic modifier in the control of rig-i initiated inflammatory response, so when we analyzed the response you can

see there is repeat production, all the expression of the interferon and also accordingly increased phosphorylation of irf3, you can see the beginning of the innate response but it's efficient role to activate the production of the interferon. this is after 8 hours after.

however you can see there is continuous increase of the rig-i protein, even 24 hours after viral infection. so what's the association of the increase of decreased expression of interferon and rig-i molecule, there must be a molecule to terminate the

reincarnation of pathogenic rna by the rig-i, so they can not initiate the phosphorylation of the irf-3, we find rna which could be bound to the rig-i. and actually, rig-i is the rna binding protein. so we figure out the one molecule and there's no binding

of the 3, the rig-i, there's a dramatic binding between them after viral infection, so we can see here this deficient mouse resistant to viral challenge with increased survival and also dramatic production of interferon in the blood and also accordingly there is less t cell

daniel in the deficient mouse. and make the story short, we find this molecule binds to the ctd of the rig-i, so that's the later stage of innate response, there's upregulation of the coding rna 3b which binds to the rig-i which competitive with the rna to terminate the

recombination of the rig-i to the pathogenic rna, then it terminates initiation of phosphorylation of the ilf 3 by rig-i, so this is just one mechanic of the immune system. the cells are innate, can timely terminate the innate inflammatory response as the

later stage by disrupting the function of the rna center, so it's helpful to understand how self help about help our self to maintaining maintenance of immune system, this is the ongoing research in my laboratory, trying to identify the coding rna and binding

protein in the inflammation, immune suppression, cancer immunotherapy, we just now identified several rna binding, coding rna, and also no time to -- i have no time to present, we identified in the dendritic cell which incorporates

incorporate-dc. this is a translational study of the molecule in cancer the hepatocellular carcinoma is high in china with mortality, interferon adjuvant therapy only benefits a limited part of the liver cancer patients. we collected tissue samples of

the normal liver and fibrotically, hepatocellular carcinoma and hepatocellular carcinoma tissue from patients. we did the micro to identify the good marker to predict the prognosis of liver cancer. this is the cancer story. cancer story paper four years

ago. and we also are very interested how we can figure out the patients who are response to offering to the survey. so we identified the rsc per file after the -- in the hepatocellular carcinoma treated by the operator interferon.

you can see here, and we collected the tissue samples from liver cancer patient and then also did the micro urea analysis, you can see several rsc downregulated, among them one molecule attract our attention, rig-i, so we ask the rig-i?

liver cancer prognosis? and especially in the interferon therapy of this -- of the so we decided the rig-i expression in the liver tissue, and we also confirmed this. there is a decreased expression of rig-i in the liver cancer -- in it the liver cancer tissue

through different cohort. and also we analyzed the expression of the rig-i in the liver cancer tissue with the survival of patients. you can see with high suppression of rig-i in the liver cancer tissue the patient will have the pronounced overall

survival. two independent cohorts to show this. and also how about interferon therapy, you can see here if you have overall survival of the cancer patient, after interferon, when you distinguish the patients into two groups,

one has a high expression of rig-i in cancer tissue, these patients will be -- will have the prolonged survival after interferon therapy. if the patient has a lower suppression of the rig-i in the tissue, they have no response to so the rig-i expression level

may be the good marker to predicate the responsivity of interferon in this part of the cancer patients. the rig-i combined to the y, preventing the dephosphorylation of the tet1 by shp1, it can maintain phosphorylation status and promotes the nuclear

translocation of the stat1 in interferon stimulation so the rig-i, the rna sensor, can be -- can act as the tumor suppressor, and also utilized as biomarker of the interferon therapy at least in the liver cancer also would further analyze why the liver cancer, the low

expression of the rig-i in liver cancer, and we try to provide actually partially were most liver cancer patients are men, not women, so we detected there is high compression of rig-i in normal liver of women population, and very low in the men.

so this is just provides -- at the same time, it also indicates why the women population have increased incidence of auto inflammatory disease such as lupus with increased production of interferon. another story about toulac 3, we have so many reports about the

trr expression on tumor cell, ten years ago we have two papers showing the tumor cell can express toulac 4, and that can increase resistance of the cancer cell and promote the capacity of the cancer cell. now we want to address the host toulac receptors in the tumor

metastasis, especially in the organ, so we asked this question by challenging the toulac deficient mouse by inoculating the lowest cancer cell and b-cell melanoma subcutaneously and observed spontaneous lung metastasis by removing the primary tumor.

you can see here there's less pulmonary metastasis in the toulac 3 deficient mouse and less pulmonary metastasis, we're now confirming this. now we show experiment it's about the toulac 3. you can see there is magic lung metastasis in the toulac 3

deficient mouse but not the 4 and 9. this is a significant decrease of the lung metastasis. and we can see here tlr 3 the mouse had longer survival after tumor inoculation. and importantly the new concept for cancer metastasis, ten years

ago proposed. the primary tumor can indicate the distant organ for creating the favorable environment for the future metastasis by releasing the factors in the blot. so there are so many markers for, for mp9 or b or 8, so we

detect the expression of the pre-niche markers in the lung, especially the 3 deficient. ths a dramatic decrease of the markers in the tlr3 deficient mouse and decreased expression of fibronectin. so what's the mechanical response for this?

make a story short, we analyze different types of immune cells, finally we find the neutrophils involved in this, we can see after inoculation tumors cells decreased improvement of neutrophil to the lung, however without toulac 3 there's less neutrophil recruited to the

long. we also find decrease of spleen in the presence of the blots but not in the bone marrow. so we detected the neutrophil tracking chemokines, you can see here there's lower level of chemokine in the serum, and also

in the path of the toulac deficient mouse in response to tumor challenge, you can see. so the toulac 3 deficiency prevents pre-measured information and spontaneous metastasis by reducing to the lung. what's the decreased expression

of the chemokine production and impaired neutrophil recruitment, by performing the bone marrow transplantation we confirm toulac 3 expression in the stroma is responsible for this phenomenon. at first we're have had in the tlr3, finally it was night.

the stroma cell in the lung will be responsible for the neutrophil recruitment. then we analyzed the expression of the tlr3 different type of immune cell in the lung, we found it's not the immune cell, it's the highly expression of tlr3, it's the envelope type 2

epithelial cell express high level of tlr3 and rescue the expression in the lung, pressurely in the tlr3 deficient nows and found here we can see it can rescue the neutrophil recruitment and allow metastasis, and by the tlr3 and is it possible for neutrophil

when we delete neutrophil and also reduce the metastasis, tlr3 expression, chemokine production and neutrophil recruitment responsible for increased lung metastasis. epithelial tlr3 is critical for lung metastasis, and then we ask a question, what's the molecule

responsible for the tlr3 activation? the primary tumor, is a long distance, so the primary tumor must release some soluble factors, then it can indicate the last microenvironment by this releasing factors. as we know, they can inhibit

immunoresponse and also indicate immune system to be favorable for their escape, especially by inducing immune suppression. so we isolated the tumor exosome and injected them to the normal mouse. you can see here this exogenous with the epithelial cell and

confirm this tumor exome with upregulate tlr3 expression the epithelial cells leading to increased production of chemokines. result, tlr3 there's less production of chemokine, so the episomes with induce chemokine production by epithelial cell

while tlr3. then we also analyzed the markers expression in the mouse, you can see here increased expression of the fibronectin in the wildtype mice. however, less expression of the the fibronectin in tlr3 deficient mouse after excision

of tumor exosome. tumor exosome can also upregulate fibronectin in the and the phenomenon was observed for the chemokine production, and also neutrophil recruitment and allow metastasis. so what's the molecules in the tumor exosome?

we treat the tumor exosome, treatment with rnaase, tlr3. and responsive for chemokine production, rna-seq of the tumor exome mrna we found there are enriched small nuclear mrna and translated this finding to the clinic and we find high

expression of tlr3 in the lung cancer correlates the massive neutrophil infiltration and also more tlr3 expression correlated with the increased production of pro metastatic expression, it's called s100a 2 and amountever of amount ever ever ever amount ever of ever are are 2 -- a2and a-7,

shortened cancer of the lung to make a story -- to summarize the story, primary tumor which contain rna, especially small nuclear rna can circulate to the lung, upregulate tlr3 expression and activate tlr3 in the tet2 epithelial cell leading to expression of chemokine,

specially neutrophil, attract neutrophil, then reproach more neutrophil to the lung, so forming the pre-niche favorable tumor and promote cancer metastasis, we just identified one molecule tlr3 in the formation of the pre-metastatic niche, so many molecules must be

involved in the recruitment of the tumor promoting cells, mdsa regulatory t cells, regulatory b-cells, type 2 macrophages and even the population of human myeloid bone marrow myeloid cells. so we should pay much attention to identify sectors which can

drive formation of pre-metastatic niche especially in distant organ with cancer we also summarized the six characteristics of pre-metastatic niche, and two of them are inflammation and immune suppression, and also they are several molecules involved in

the genesis and vascular permeability, and also involved in the genicity. however we should identify immune suppressive cell and inflammatory molecule in the process of the formation of forming of the pre-metastatic niche especially driving the

stroma cell with upregulation of the pre-metastatic molecule, so if we identify this we can block it and reduced expression of the pre-metastatic molecule, then especially together with adaptive new transfer of blockade must be improved clinical outcome of the cancer

so this is what i want to report to you. finally i want to thank the students in my laboratory, especially dr. yanfang lui and yan gu and dr. jin hou for the story in liver cancer. thank you for your attention. [applause]

>> so i'm sure dr. cao would be happy to answer questions. >> it's a very nice story. actually we know including the viral sectors (indiscernible) the tlr3 can recognize rna, it's different from the host rna for your star date you show there receptor can recognize tumor

cell generated rna, so because of the tumor cell is generated from our host cell, so what's the difference of the rna recognized by the tlr3 with bacteria. >> good question. actually we did not find the signature of the tumor derived

rna responsible for tlr3 reconnection and activation, we tried to do this. however there are so many mutants in the tumor cell cell, must be different with the formal cell so we have the rna-seq data, we find the rna fractions are enriched of the

small nuclear rna, different from the profile from the normal epithelial cell, so now we have new advance tool to figure out what kind of pathogenic rna generated by the tumor cell, and i have to mention that the rna sensor can recolonize the cell rna in normal, so example the

rig- i, the story, combined to the coding rna sn 3-b, repeatedly released, there's no affinity to activate the atp activity of rig-i, and release -- and also release autoinhibitor look, so binding affinity of the rna will determine the outcome of the

molecule in the pathogenetic process or the physiologic process. >> thank you. >> over here, very beautiful story. so as you know, many things are double-edged swords, and one of them i guess could be tlr3.

so poly-ic, as you know, is a very good adjuvant and acting through tlr3 to activate dendritic cells and antigen presentation and so forth but you also described how it's involved in recruiting recruiting neutrophils, whether it might be possible to improve the

adjuvanticity of something like poly-i-c to induced tlr3 by blocking the chemokines that recruit recruit neutrophils, beneficial effect without adverse effect. >> thank you for the very important question. so actually, this is the two

faces of the innate molecule in tumor progression and cancer so there are also two faces of the neutrophil in cancer. actually the neutrophil can kill the tumor cell, especially activated by the adjuvant molecule. however, naturally especially in

the chronic inflammatory process, the neutrophil, maybe they have different subsets of the neutrophil secreting, so the natural neutrophil can promote cancer metastasis confirmed by several laboratory, so poly-i-c after in vivo especially in tumor tissue can activate

inflammatory response which also so many innate immune cells can work together to kill the immune -- to kill the tumor cell. however, in the natural process of the tumor metastasis, the tumor, primary tumor, can infiltrate the tumor cell, not

the tumor, the stroma cell, to are favorable, so this is the depending on the strength of one molecule action and to the size of the one molecule so they are functioning and also the role they will act to play. this topic is very close my heart, too close for comfort.

i've been in the inflammation research for the last 35 years. i came to this institution and struggled heavily to promote the role of inflammation in cancer which was heavily opposed, rejected, downplayed, and now i see everywhere that inflammation has something to do with it.

and i notice a comment and then a question is that the yin and yang of inflammation that you mention was introduced to the "nature" journals, several journals in 2006, 2007, i finally published in 2008. with regard to the eosinophil, i mean the dendritic cells and

macrophages you mentioned, if you are genetically modifying the macrophages, have you noticed any compensatory mechanisms that other innate immune systems gets involved, because this is what we have seen the interaction and synergies between the host

immune cell and then interaction with activation of eosinophil infiltration and then macrophage infiltration that leads to the first evidence for direct link between inflammation and tumor development which i paid heavily for promoting, even through the liver channels.

>> thank you for the good comments. and as for the role of the macrophage in cancer, immune response of the immune escape, they are (indiscernible) and i think this is a good topic to be further investigated. >> yes.

>> inflammatory adjuvant can polarize the tet2 macrophage generation, and especially in the tumor microenvironment, which can feedback promote cancer metastasis and also render the tumor cell more resistant to the reduction. however, some researchers tried

at first to polarize the tet1 macrophage generation, in the tumor microenvironment. so trying to utilize the tet1 cytokines to activate their function, i think several molecules involved in this. i cannot remember exact name but they are approached to change

the tumor-promoting status of macrophage to the tumor-killing status of macrophage in the tumor environment. >> in 1 and 2, right. >> yeah, just one case about the dendritic cell in the tumor environment, it's very established too that dendritic

cell in the tumor microenvironment (indiscernible) however two years ago there are cell reports about the cd1 or 3 positive cell which can initiate t cell response, even in the environments of the tumor tissue. so there must be some

tumor-killing immune subsets including macrophage of dendritic cells in the tumor microenvironment. >> one last question. >> i'm in the ibcr, newcomer in the inflammation skills, so it's my great opportunity to get the instruction.

my question is whether you have any comment on the epithelial mesenchymal transmission with infection with inflammation cause emt is also good model for the cancer, so i'm thinking about this. >> so i'm not very familiar with emt, i'm sorry.

i think there are two kind of cells, resident immune cells and migratory immune cells which can interact with the stroma in the distant organ. i think epithelial cells, endothelial and other kind of cells, stroma cells, must be interactive to the immune cells.

not only to the cell to cell direct contact but also can interact by the factors secreted by two kind of cells, i think they number -- i think how to say it, the inflammatory response to the factors released by the immune cells, especially immune suppressant cell not

process of tumor genicity or tumor metastasis. >> thank you. >> let's thank our speaker for an outstanding presentation. there's a reception in the library, if you have additional questions i'm sure xuetao will be happy to answer them.