1. Endogenous T Cell Responses to
Antigens Expressed in Lung
Adenocarcinomas Delay Malignant
Tumor Progression
BY Dupage M., Cheung A. F., Mazumdar C., Winslow., Bronson
R., Schmidt L M., Crowley D., Chen J., Jacks T
Presented By Surayya Sana
2. Introduction
Cancer Immuno-editing
● Interaction Between Immune system
● Tumor cells Progression of tumor
– Elimination
– Equilibrium
– Escape
● Tumor Metastatic Malignant
How Do Tumor Escape Immune surveillance?
3. Main Points
• T cell responses against autochthonous lung tumors delay malignant
progression.
• Transplantable lung tumor models prime protective T cell responses.
• Vaccination against antigens in autochthonous tumors promotes tumor
protection.
• Transplantation of cell lines derived from lung cancer and vaccination against
autochthonous tumor results in tumor that lose antigen expression.
4. Models Used To Study Cancer
● Transplantation of Primary or Cultured Tumor Cells
– Introduce large number of tumor cells (grow rapidly)
– Traffic cells directly to lymphoid organs
● Carcinogen-Induced Models
– Focused predominantly on sarcomas
– Tumors are expected to harbor large number of mutations
– Leads to artificially robust immune system
● Transgenic Mouse Model
– Develop Tumors Spontaneously
– Express tumor antigen throughout targeted organs
– Antigenic expression in normal tissue likely alters T cell response.
– Fail to fully immune response against human disease.
● Genetically Engineered Mouse Models
– Recapitulate genetic of human disease/cancer
– Provide Spatiotemporal control of tumor onset.
5. Induction Of Autochthonous Lung Tumors
Inhalation of lentiviral vectors expressing
Cre recombinase
Production of Autochthonous
Lung tumors
Main Point: Combination of activated Ras and deleted p53 = Highly oncogenic
6. Induction of Lung Tumors Using Lentiviral Vectors
Cre (Lenti-x) was used to indiced tumors
that lack expression of model antigen.
Luc OS: T cell antigen fused to C-terminal
(3’ end) of Luciferase gene.
Amount of Infiltrating Lymphocytes
Large amount of infiltrating Lymphocytes at 8 weeks with Lenti-lucOS.
Tumor Infiltrating Lymphocytes growth decreased after 8 weeks.
7. T Cell Responses to Tumor Antigens are generated but not Sustained
Increase in antigen specific T-cell in Lenti-LucOS Tumors.
Negative
control
Positive control (Influenza
virus)
8. T cell Response to Tumor Antigens are Generated but not Sustained
Non
functional
Functional
PD-1: Exhaustion marker for T cell
9. Adoptively Transferred T Cells are not fully functional in
Response to Established Tumors
Naive T cells are activated and Proliferated after 3 days.
3 days after transfer of naive OT-I Cell
14.3
10. Adoptively Transferred T Cells are not fully functional in Response
to Established Tumors
Activated and Proliferated naïve2C cells after three days of transfer
Naïve 2C cell after three days of trasnfer
11. Adoptively Transferred T Cells are not fully functional in
Response to Established Tumors
DLN Lung
After 12 days of Transfer
13.7
Analysis of OT-1 T cells 7 days after WSN-
SIN infection
Even though T cells can be stimulated to
proliferate and migrate tumors. Only few T
cells continue to have the capacity to
produce effective cytokines in response to
tumors.
12. Antigen Expression and Presentation is Maintain in
Tumors
Comparison of luciferase level between
immuno-competent and immune
compromised mice.
Luciferase Assay
Reduction in MHC class I expression in Lenti-LucOS tumor with tumor
Progression
13. Immunogenic Tumor have Delayed Tumor Progression
Tumor Grading
Difference in size between
immunogenic and non immunogenic
tumor requires the presence of
adaptive immune system.
Lenti-Luc OS tumor were lower grade compared to Lenti-x tumor
15. Transplanted Lung Tumors Induce strong T cell Response that Force
Tumor Elimination or Tumor Antigen Loss
Reduction of tumor volume and antigen
expression upon transfer of naïve OT-1/2C
cells into immune compromised mice.
Loss of antigen
expression upon
transplantation in a T
cell.
Transplantation into
a tumor native site
can drive tumor
antigen loss.
16. Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and
Promotes Loss of Antigen Expression
Experiment
Inject DC2-4-LusOS
Lenti-x or Lenti-LucOS
Generation of
Autochthonous
Tumor
After Vaccination: Reduction in Lenti-LucOS
tumor and antigen expression in Lenti-LucOS
Tumor.
17. Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and
Promotes Loss of Antigen Expression
Increased in functional T cell response in tumor after vaccination.
18. Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and
Promotes Loss of Antigen Expression
CD44+ CD127+ : memory like
CD44+ CD127:effector like
19. Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and
Promotes Loss of Antigen Expression
Delayed tumor growth and retention of infiltrating lymphocytes in
vaccinated mice.
20. Statement of Major Question
How much this vaccination can help to cure
Autochthonous lung tumor in future?
