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

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?

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.

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.

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

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.

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)

T cell Response to Tumor Antigens are Generated but not Sustained

Non

functional

Functional

PD-1: Exhaustion marker for T cell

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

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

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.

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

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

Immunogenic Tumor have Delayed Tumor Progression

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.

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.

Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and

Promotes Loss of Antigen Expression

Increased in functional T cell response in tumor after vaccination.

Vaccination in Autochthonous Lung Tumor Reduces Tumor Burden and

Promotes Loss of Antigen Expression

CD44+ CD127+ : memory like

CD44+ CD127:effector like

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.

Statement of Major Question

How much this vaccination can help to cure

Autochthonous lung tumor in future?

References

● http://www.cell.com/cancer-cell/abstract/S1535-6108(10)00479-4

● http://theoncologist.alphamedpress.org/content/4/3/263.full