CN109813913A - New opplication of the aromatic hydrocarbon receptor (AhR) in prediction immunotherapeutic effects - Google Patents
New opplication of the aromatic hydrocarbon receptor (AhR) in prediction immunotherapeutic effects Download PDFInfo
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Abstract
The present invention provides a kind of new opplication of the aromatic hydrocarbon receptor (AhR) in prediction immunotherapeutic effects, specifically, the present invention provides AhR as target in exploitation, screening and/or prepares application in drug for treating tumour, the reagent for additionally providing inhibition, silencing and/or knockout AhR is preparing the application in the drug for treating tumour, and the reagent for additionally providing detection AhR level is preparing the application in the detection agent for predicting immune detection point inhibitor for treating tumor effect.
Description
Technical field
The present invention relates to a kind of new opplications of transcription factor aromatic hydrocarbon receptor (AhR), specifically, being about aromatic hydrocarbon receptor
In the application of the detection method and the target as anticancer drug with prediction immunotherapy medicaments therapeutic effect, belong to medical neck
Domain.
Background technique
Aromatic hydrocarbon receptor (aryl hydrocarbon receptor, AhR) is a kind of transcription factor, can be by under regulation
The transcription for swimming gene plays the metabolism of the compounds such as Polycyclic Aromatic Hydrocarbonat Existing in Environment, immunity of organism, the rhythm and pace of moving things, reproduction, oxidative stress etc.
Important regulating and controlling effect.AhR be present in lung, liver, kidney, placenta, tonsillotome, skin, bone-marrow-derived lymphocyte of human body etc. it is various tissue and
In cell, tryptophan metabolite, heme catabolism product, arachidonic acid metabolite etc. are its endogenic ligands.
The maintenance and stabilization of AhR participation body immune system.Although AhR knock out mice will not be dead, its internal organ
Often depauperation, spleen enlargement, B cell increase, IFN γ and IL-12 generation increase for tissue and immune system.AhR can lead to
It crosses ligand-dependent mode and adjusts immune cell function, such as CD8+T cell, Dendritic Cells, Treg cell, macrophage.?
Under dioxin processing, CD8+T cell activity caused by AhR can inhibit virus prime to infect, but the memory CD8 special to virus
The activity of+T cell is without influence.AhR missing cause Lang Gehansi maturing dendritic cell obstacle, costimulatory molecules CD40, CD80,
CD24a expression is low, but its phagocytic activity is higher.AhR can also influence Dendritic Cells (DC) and immune be answered by what T cell mediated
It answers.AhR can change the distribution situation of Treg, increase the ratio of Treg in spleen to inhibit immune response.AhR may also participate in tune
It controls the synthesis secretion of monocytes/macrophages cell factor, enhancing monocytes/macrophages bactericidal effect, reduce monocytes/macrophages
Apoptosis.The ability of lung qi bubble CD4+T cells against viral can be enhanced in AhR.AhR can raise the expression of NF- κ B and its DNA is combined
Ability, to enhance inflammatory reaction.AhR can also regulate and control the expression of IL-1 β, IL-6 and TNF-α etc. to play immune negative tune
Control effect.AhR can enhance oxidative pressure intracellular and promote the proliferation of lung carcinoma cell, and protection lung adenocarcinoma cell resists tobacco particle object
Redox reaction.The chemotactic factor (CF) that AhR mediation environmental carcinogen polycyclic aromatic hydrocarbon is caused, pulmonary epithelial cells are secreted
CXCL13, the latter play a significant role in the generation of lung cancer.But effect of the AhR in immunization therapy is still unclear.
In recent years, molecular targeted agents late make us in the clinical application of non-small cell lung cancer (NSCLC) patient by acquirement
The progress attracted attention, but its prognosis is still unsatisfactory, still needs to explore new treatment method, to obtain the new breakthrough of lung cancer therapy.?
In cancer immunotherapy, inhibiting immunologic test point access is considered as one of most promising therapeutic modality, and mechanism is to pass through
Related target (PD-1, PD-L1, CTLA-4) in access is inhibited to release the suppressed state of T cell activity, the T cell after activation can
Attack and tumors destroyed cell.PD-1/PD-L1 immunotherapy is the new class anticancer immunotherapy currently to attract attention, it is intended to
Cancer is resisted using the immune system of human body itself, by blocking PD-1/PD-L1 signal path to make cancer cell death, has and controls
The potentiality for treating multiple types tumour are expected to substantive improvement patients overall survival's phase (OS).And major pharmacy giant is also at top speed
Respective project is promoted, single medication is investigated and combination treatment is used for the treatment of kinds cancer, to excavate the maximum of such drug
Clinical potentials.Though PD-1/PD-L1 antibody is wide spectrum medicine, not all patient can have response to PD-1/PD-L1 antibody.Mesh
Come to see, the 30%-40% in melanoma cancer patients can benefit from PD-1/PD-L1 Antybody therapy, non-small cell lung
The response ratio of cancer is 20%, and the preliminary data of liver cancer is also 20%, and clear-cell carcinoma is probably 20% to 30%.
In order to solve the problems, such as that PD-1/PD-L1 antibody is efficient relatively low in process of clinical application, there is an urgent need to find
The new method of PD-1/PD-L1 antibody curative effect is predicted, precisely to screen effective case.Meanwhile significantly increasing PD-1/PD-L1 antibody
The drug of curative effect is also badly in need of by clinic.
Summary of the invention
It is an object of the present invention to provide a kind of detection techniques for predicting Immuno Suppressive Therapy effect, and can show
Write the drug targets of enhancing tumour immunotherapy therapeutic effect.
Inventor has found that AhR is the suitable targets of kinds cancer treatment under study for action, and AhR inhibitor can be used individually
, can also be with immunotherapy use in conjunction in the treatment of cancer, and AhR inhibitor and immunotherapy have apparent synergistic effect,
The curative effect that immunotherapy can be enhanced, overcomes the drug resistance of immunotherapy, to play stronger therapeutic effect, mentions for the treatment of tumour
New therapeutic strategy is supplied.Inventor's further study show that AhR expression height and Immuno Suppressive Therapy effect phase
It closes, the curative effect that AhR expresses high patient P D-1 antibody is preferable, the expression of cancerous tissue AhR is detected using ImmunohistochemistryMethods Methods,
It can be used as an important means of prediction Immuno Suppressive Therapy effect.
To, on the one hand, the present invention provides AhR in exploitation, screening and/or to prepare for treating tumour as target
Application in drug.
On the other hand, the present invention also provides the reagents of inhibition, silencing and/or knockout AhR to prepare for treating tumour
Drug in application.
Specific embodiment according to the present invention, in technical solution of the present invention, the tumour include but is not limited to lung cancer,
Cervical carcinoma, oophoroma, liver cancer, the cancer of the esophagus, gastric cancer, colon and rectum carcinoma, melanoma, Huppert's disease, incidence squamous
Cell cancer, prostate cancer, leukaemia, lymthoma, brain tumor, cutaneum carcinoma.
Specific embodiment according to the present invention, in technical solution of the present invention, the tumour includes immunotherapy sensitivity
And drug resistant cancer.
On the other hand, the present invention also provides the reagents of detection AhR level to prepare for predicting that immune detection point inhibits
The application in the detection agent of tumor effect is treated in agent.
Specific embodiment according to the present invention, in technical solution of the present invention, the immunologic surveillance point include PD-1,
One of PD-L1, CTLA-4 or a variety of.
Specific embodiment according to the present invention, in technical solution of the present invention, detection AhR level includes detection AhR
Gene expression dose, or the protein expression level of detection AhR.Can using known any feasible method in fields into
Row detection, it may for example comprise but be not limited to, using immunohistochemistry or the method for Western blot, detect AhR in tissue of patient
Expressing quantity.Polymerase chain reaction, expression quantity and montage sheet of the detection AhR in gene level can also be used.It is horizontal to detect AhR
Reagent include but is not limited to detection reagent used in these detection methods.
Specific embodiment according to the present invention, in technical solution of the present invention, the treatment tumour include by inhibiting,
It silencing and/or knocks out AhR and treats tumour, or by inhibition, silencing and/or knock out AhR and immunotherapy use in conjunction and control
Treat tumour.
As previously mentioned, the tumour includes but is not limited to lung cancer, cervical carcinoma, oophoroma, liver in technical solution of the present invention
Cancer, the cancer of the esophagus, gastric cancer, colon and rectum carcinoma, melanoma, Huppert's disease, head and neck squamous cell carcinoma, prostate cancer,
Leukaemia, lymthoma, brain tumor, cutaneum carcinoma.In some specific embodiments, the tumour includes that immunotherapy is sensitive and resistance to
The cancer of medicine.
On the other hand, the present invention also provides a kind of pharmaceutical composition for treating tumour, the pharmaceutical composition include inhibit,
Silencing and/or the reagent for knocking out AhR, further include immunologic surveillance point antibody.In some specific embodiments, the immune prison
Measuring point antibody is preferably PD-1 and/or PD-L1 antibody.The experimental results showed that AhR inhibitor and PD-1/PD-L1 antibody have very
Good combined effect.Specifically, any conjunction such as tablet, injection can be made by mixing AhR inhibitor with adjuvant appropriate
The medicament of conformal formula, alternatively, AhR inhibitor and PD-1/PD-L1 Antibody preparation combination drug are mentioned for the immunization therapy of cancer
For new method.
In specific embodiments of the present invention, present invention discover that AhR causes PD-L1 to increase and promote lung cancer to send out in smoking
Key effect is played in life, providing AhR can be used as the evidence for the treatment of of cancer new target drone, and it was found that AhR is in tissue of patient
Expression quantity can predict patient well to the therapeutic effect of tumour immunotherapy, AhR is in prediction immunotherapy of tumors effect
In significant application value effect.
Detailed description of the invention
Figure 1A~Fig. 1 D shows that tobacco and BaP promote the experimental result of the expression of PD-L1 on a cellular level.Wherein, scheme
1A, tobacco extract handle H460 cell and 16HBE cell, and real-time PCR detects the expression of PDL1.Figure 1B, tobacco mention
Object processing H460 cell and 16HBE cell are taken, flow cytometer showed detects the expression of PDL1.It is thin that Fig. 1 C, various concentration BaP handle H460
Born of the same parents and 16HBE cell, real-time PCR detect the expression of PDL1.Fig. 1 D, 5 μM of BaP processing H460 cells and 16HBE cell,
Different time sections collect cell, and real-time PCR detects the expression of PDL1.
Fig. 2A~Fig. 2 C shows that tobacco and BaP promote the experimental result of PD-L1 expression in level in animal body.Wherein,
The method detection mouse lung sample tissue of Fig. 2A, air/tobacco processing different time stage A/J mouse, immunohistochemistry are cut
The expression of the PDL1 of piece.The method detection of the A/J mouse in Fig. 2 B, BaP/ corn oil processing different time stage, immunohistochemistry is small
The expression of the PDL1 of mouse lung sample histotomy.In Fig. 2 C, immunohistochemistry and Immunofluorescence test mouse lung sample tissue
The expression and positioning of PDL1 and TTF1.
Fig. 3 A~Fig. 3 B shows that PD-L1 survival region of high expression and lung cancer patient in smoking lung cancer patient is negatively correlated
Experimental result.Wherein, Fig. 3 A, with anti-PDL1 and Actin antibody to the cancerous tissue (T) of 62 lung cancer patient samples and from same
The corresponding cancer beside organism of an example patient (N) carries out Westernblot analysis, and the expression of 10 samples, number are shown in figure
Corresponding patient number.Fig. 3 B carries out Kaplan- to PDL1 high expression and the survival region relationship of lung cancer patient with SPSS software
Meier survival analysis, long-rank are examined, p < 0.05.
Fig. 4 A~Fig. 4 B display, which knocks out AhR, can slow down the experiment of the generation of lung cancer caused by BaP and the expression of PD-L1
As a result.Wherein, Fig. 4 A, BaP/ corn oil processing different genotype C57 mouse (AhR+/+、AhR+/-、AhR-/-), lung microCT
(on), HE dyeing result (in) and immunohistochemistry detection BaP/ corn oil processing different genotype C57 mouse lung tissue in
PDL1 expression (under).Fig. 4 B, the expression and positioning of AhR and PDL1 in 3 lung cancer patient tissues of Immunofluorescence test.
Fig. 5 A~Fig. 5 B shows that AhR inhibitor significantly inhibits the growth of mice lung cancer and has with PD-L1 antibody good
The experimental result of combination therapy effect.Wherein, Fig. 5 A, C57 mouse tail vein are inoculated with LLC cell, micro-CT and HE dyeing inspection
Survey the influence after ANF vivo medicine-feeding to mouse tumor volume.Fig. 5 B, C57 mouse tail vein be inoculated with LLC cell, micro-CT and
Influence after the HE dyeing detection antibody combined vivo medicine-feeding of ANF and PDL1 to mouse tumor volume.
Fig. 6 A~Fig. 6 B shows that AhR inhibitor has apparent treatment PD-L1 antibody sensitivity and PD-L1 antibody drug resistant small
The experimental result of the anticancer activity of mouse solid tumor models.Wherein, Fig. 6 A, MC38 inoculate C57 mouse, take out after experiment
The tumor tissues of mouse simultaneously take pictures and show the inhibitory effect of ANF Yu PDL1 antibodies on tumor size.Fig. 6 B, Ag104Ld notch graft
Kind of B6C3F1 mouse takes out tumor tissues of mouse and taking pictures and shows ANF and PDL1 antibodies on tumor size after experiment
Inhibitory effect.
Fig. 7 shows that the expression of AhR in clinical patient sample predicts the experiment knot of the curative effect of PD-1 antibody well
Fruit.In figure, PR: alleviate (partial response) in part；SD: stable disease (stable disease)；PD: progression of disease
(progressive disease)。
Specific embodiment
Below by way of the beneficial effect of the specific embodiment implementation process that the present invention will be described in detail and generation, it is intended to which help is read
Reader more fully understands essence and feature of the invention, does not limit the scope of the present invention.In embodiment, it is not specified
The experimental method of actual conditions is conventional method and normal condition known to fields, or according to proposed by apparatus manufacturer
Conditional operation.
Embodiment 1
The influence that tobacco smoke exposure expresses PD-L1 is currently without report.In the present invention, tobacco is prepared using aerosol producer
Extract (CES), smog are dissolved in 1640 culture mediums of 50mL serum-free.By tobacco extract (CES) and tobacco carcinogenic substance
The normal lung epithelial 16HBE cell of BaP (BaP) (sigma) processing and non-small cell lung cancer H460 cell.As a result referring to Figure 1A
~Fig. 1 D.Wherein, Figure 1A, tobacco extract handle H460 cell and 16HBE cell, and real-time PCR detects the table of PDL1
It reaches.Figure 1B, tobacco extract handle H460 cell and 16HBE cell, and flow cytometer showed detects the expression of PDL1.Fig. 1 C is different dense
BaP processing H460 cell and 16HBE cell are spent, real-time PCR detects the expression of PDL1.Fig. 1 D, 5 μM of BaP handle H460
Cell and 16HBE cell, different time sections collect cell, and real-time PCR detects the expression of PDL1.Tobacco mentions as the result is shown
After taking object to handle, the mRNA level in-site and protein level of PD-L1 is all significantly raised, and at the expression quantity of PD-L1 and tobacco extract
It manages the time and dosage is presented and is positively correlated.It is consistent with tobacco extract that BaP handles cell results.These results suggest that tobacco is extracted
Object and BaP promote the expression of PD-L1 on a cellular level, increase degree and tobacco extract processing time and dosage in positive
It closes.
In order to which horizontal further verify caused by smoking and BaP changes in vivo, the present invention carries out real on A/J mouse
It tests, mouse is made to be exposed to the smog that simulation people's smoking of aerosol producer suction fuel cigarette generation generates, method is daily smoking 12
It props up (as people's smoking, every cigarette is discontinuously inhaled 3 minutes, then feeds back pure air 15 minutes), expose 5 days weekly, continuously
Exposure 3 weeks to 24 weeks, then takes mouse lung tissue, is examined by real-time quantitative RT-PCR, immunohistochemistry, Western blot method
Survey PD-L1 situation.As a result A~Fig. 2 C referring to fig. 2.Wherein, Fig. 2A, air/tobacco processing different time stage A/J mouse,
The expression of the PDL1 of the method detection mouse lung sample histotomy of immunohistochemistry.When Fig. 2 B, BaP/ corn oil processing difference
Between the stage A/J mouse, immunohistochemistry method detection mouse lung sample histotomy PDL1 expression.Fig. 2 C is immunized
The expression and positioning of PDL1 and TTF1 in groupization and Immunofluorescence test mouse lung sample tissue.As a result, it has been found that smoking can make
The expression of PD-L1 is significantly increased；In addition, mouse (each dosage 100mg/kg weight, twice a week continuous 5 weeks) is handled with BaP,
Then the expression of mouse lung tissue detection PD-L1 is taken, discovery BaP processing can be such that the expression of mouse lung tissue PD-L1 significantly increases
It is high.
By the expression of PD-L1 in 62 patient's cancerous tissues of detection, present invention discover that advanced lung cancer patient (the III phase
With the IV phase) in PD-L1 expression obviously compare early stage patient (I phase and II phase) height；With Kaplan-Meier method analysis patient's
Life span, as a result referring to Fig. 3 A~Fig. 3 B.Wherein, Fig. 3 A, with anti-PDL1 and Actin antibody to 62 lung cancer patient samples
Cancerous tissue (T) and 10 marks of display in cancer beside organism (N) progress Westernblot analysis corresponding with an example patient, figure
This expression, the corresponding patient number of number.Fig. 3 B, with SPSS software to the survival region of PDL1 high expression and lung cancer patient
Relationship carries out Kaplan-Meier survival analysis, and long-rank is examined, p < 0.05.As a result, it has been found that the highly expressed pulmonary carcinosis of PD-L1
The people living phase is significantly shorter than PD-L1 low expression patient (p < 0.05), illustrates that the survival region of PD-L1 high expression and lung cancer patient is negative
It is related.
PD-L1 is caused to increase and cause the effect in lung cancer in order to assess AhR in smoking, the present invention knocks out small using AhR
Mouse (Jackson Laboratory), rationally grouping after with carcinogenic substance BaP processing (BaP 100mg/kg, twice a week, continuously
8 weeks), and with toy computed tomography (Micro-CT), lung tissue HE dyeing, immunohistochemistry etc. detect, as a result referring to
Fig. 4 A~Fig. 4 B.Wherein, Fig. 4 A, BaP/ corn oil processing different genotype C57 mouse (AhR+/+、AhR+/-、AhR-/-), lung
MicroCT (on), HE dyeing result (in) and immunohistochemistry detect BaP/ corn oil processing different genotype C57 mouse lung group
Knit PDL1 expression (under).Fig. 4 B, the expression and positioning of AhR and PDL1 in 3 lung cancer patient tissues of Immunofluorescence test.Knot
Fruit discovery, which knocks out AhR, can be substantially reduced the expression up-regulation of PD-L1 caused by BaP；Wild-type mice goes out after BaP stomach-filling is handled 6 months
Show apparent tumour, and there is no tumours for AhR knockout group mouse.It is found by immunofluorescence technique, patient's cancerous lung tissue
Middle AhR and PD-L1 common high expression on lung carcinoma cell.
Then mice lung cancer cell line LLC cell is given by tail vein injection into the normal C57 mouse of immune system
The inhibitor ANF and CH223191 of AhR is handled, as a result referring to Fig. 5 A~Fig. 5 B.Wherein, the inoculation of Fig. 5 A, C57 mouse tail vein
Influence after LLC cell, micro-CT and HE dyeing detection ANF vivo medicine-feeding to mouse tumor volume.Fig. 5 B, C57 mouse tail
To mouse tumor volume after intravenous inoculation LLC cell, micro-CT and the HE dyeing detection antibody combined vivo medicine-feeding of ANF and PDL1
Influence.AhR inhibitor can obviously inhibit the progress of lung cancer as the result is shown, illustrate that AhR inhibitor has apparent anti-lung cancer
Effect；In addition, AhR inhibitor and the antibody combined application of anti-PD-L1, can significantly increase the effect of anti-lung cancer of PD-L1 antibody, the two
With good combined effect.These are as a result, illustrate that AhR is the suitable targets of lung cancer therapy, and AhR inhibitor and immunotherapy
There is apparent synergistic effect, provides new therapeutic strategy for the treatment of lung cancer.
Embodiment 2
In order to further study effect of the AhR inhibitor in the generation of other cancers, in the present embodiment, by PD-L1 high table
The mouse colonic cell system MC38 inoculation C57 mouse reached, AhR antagonist ANF treatment is given in inoculation after 4 days, after experiment
It takes out the tumor tissues of mouse and takes pictures.As a result referring to Fig. 6 A, AhR inhibitor obviously can inhibit MC38 in Mice Body as the result is shown
Interior growth, and there is good combined effect with anti-PD-L1 antibody.
It chooses PD-L1 high expression but B6C3F1 is inoculated with to the drug resistant mouse fibrosarcoma cells system Ag104ld of PD-L1 antibody
Mouse, inoculation gave AhR inhibitor combined PD-L1 Antybody therapy after 4 days, and the tumor tissues of mouse and bat are taken out after experiment
According to.As a result referring to Fig. 6 B, it is found that AhR inhibitor can reverse PD-L1 antibody drug resistance with combining for PD-L1 antibody, hence it is evident that write and inhibit
Ag104ld cell is in the intracorporal growth of mouse.These results explanation, AhR are drug resistant in PD-L1 antibody sensitivity and PD-L1 antibody
Cancer has therapeutic effect, and reversible PD-L1 antibody drug resistance.
Embodiment 3
The present embodiment has studied effect of the height of AhR expression in prediction Immuno Suppressive Therapy effect.Choose PD-
The lung cancer specimen of 1 Antybody therapy patient detects the expression of AhR and the pass of PD-1 antibody curative effect by the method for immunohistochemistry
System.The specific detection method is as follows:
1) it dewaxes: being placed in 60 DEG C of oven preheating 30min, be then respectively put into fresh dimethylbenzene I&II&III each 10 points
Clock；
2) aquation: each 5 minutes in dehydrated alcohol I&II&II, 95%, 85%, 75% ethyl alcohol each 5 minutes；
3) PBS is washed 1 time；
4) by piece be placed in citrate buffer solution repair in, micro-wave oven height fire boils 5 minutes, in low fire boil 15 minutes；
5) room temperature, about 1h are cooled to；
6) it closes: confining liquid is added dropwise, 37 DEG C are incubated for 30 minutes, remove surplus liquid；
7) primary antibody: the primary antibody covering tissue of debita spissitudo is added, 4 spend night；
8) PBS is washed 3 times, every time 10 minutes；
9) endogenous peroxydase inactivates: 3%H2O2 is added dropwise, is stored at room temperature 10 minutes；
10) PBS is washed 1 time, every time 10 minutes；
11) secondary antibody: ELIAS secondary antibody is added and covers tissue, 37 ° are incubated for 90 minutes；
12) PBS is washed 3 times, every time 5 minutes；
13) it develops the color: prepared DAB developing solution is added, is stored at room temperature 1-5 minutes, observation color terminates in due course；
14) color development stopping: tap water rinses 3 minutes；
15) it redyes: haematoxylin is added, is stored at room temperature 2 minutes, tap water rinses 20 minutes；
16) it is dehydrated: 75%, each 3 minutes in 85%, 95% and dehydrated alcohol I&II&III；
17) transparent: each 3 minutes in dimethylbenzene I&II&III；
18) appropriate mountant mounting is used, microscopically observation is simultaneously taken pictures.
As a result Fig. 7 is referred to.As the result is shown: AhR expresses the curative effect of high patient P D-1 antibody preferably (PR+SD), and AhR
The low patient P D-1 antibody unsatisfactory curative effect (PD) of expression.These results explanation, detects the expression of clinical patient AhR,
It can be used as an important means of detection immune detection point antibody curative effect.
The above is only a specific embodiment of the invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1.AhR in exploitation, screening and/or prepares application in drug for treating tumour as target.
2. the reagent of inhibition, silencing and/or knockout AhR is preparing the application in the drug for treating tumour.
3. application according to claim 1 or 2, wherein the tumour include but is not limited to lung cancer, cervical carcinoma, oophoroma,
Liver cancer, the cancer of the esophagus, gastric cancer, colon and rectum carcinoma, melanoma, Huppert's disease, head and neck squamous cell carcinoma, prostate
Cancer, leukaemia, lymthoma, brain tumor, cutaneum carcinoma.
4. application according to claim 1 or 2, wherein the tumour includes immunotherapy sensitivity and drug resistant cancer.
5. detecting the reagent of AhR level in preparing the detection agent for predicting immune detection point inhibitor for treating tumor effect
Using.
6. application according to claim 5, wherein the immunologic surveillance point includes one in PD-1, PD-L1, CTLA-4
Kind is a variety of.
7. application according to claim 5, wherein the reagent of detection AhR level includes detecting AhR water using immunohistochemistry
Flat reagent.
8. application described according to claim 1 or 2 or 5, wherein the treatment tumour includes by inhibition, silencing and/or striking
Tumour is treated except AhR, or by inhibition, silencing and/or knocks out AhR and immunotherapy use in conjunction treatment tumour；
Preferably, the tumour include but is not limited to lung cancer, it is cervical carcinoma, oophoroma, liver cancer, the cancer of the esophagus, gastric cancer, colon cancer, straight
Intestinal cancer, melanoma, Huppert's disease, head and neck squamous cell carcinoma, prostate cancer, leukaemia, lymthoma, brain tumor, skin
Cancer；
Preferably, the tumour includes immunotherapy sensitivity and drug resistant cancer.
9. a kind of pharmaceutical composition for treating tumour, which includes inhibition, silencing and/or the reagent for knocking out AhR, is gone back
Including immunologic surveillance point antibody.
10. pharmaceutical composition according to claim 9, wherein the immunologic surveillance point antibody be preferably PD-1 and/or
PD-L1 antibody.
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