the inflammatory tumor micro-environment · 2018. 10. 9. · the inflammatory tumor...
TRANSCRIPT
![Page 1: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/1.jpg)
The inflammatory tumor micro-environment:
a critical regulator of tumor development and therapy response
Inge Verbrugge Division of Tumor Biology and Immunology
Rotterdam, October 10th 2018
![Page 2: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/2.jpg)
Slide: Seth Coffelt
![Page 3: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/3.jpg)
Slide: Seth Coffelt
Part 1: Micro environmental regulation of tumor progression
Clinical Associations
![Page 4: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/4.jpg)
Rudolf Virchow (1821-1902) German Pathologist
1863: First hypothesis linking inflammation and cancer development
![Page 5: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/5.jpg)
Image: Seth Coffelt
Inflammatory tumor micro-environment in human invasive breast cancer
Question:
Can inflammation lead to cancer? Do you have examples?
![Page 6: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/6.jpg)
Chronic inflammation can promote tumorigenesis
1de Martel et al., Lancet Oncol 2012;13:607-615
Inflammatory Stimulus Malignancy
Hepatitis Virus (B and C) Hepatocellular carcinoma
Inflammatory Bowel Disease Colorectal Cancer
Asbestos Mesothelioma
Prostatitis Prostate Cancer
Schistosmiasis Bladder Cancer
H. plyori-induced gastritis Gastric Cancer
Barrett’s metaplasia Oesophageal carcinoma
Thyroiditis Papillary thyroid carcinoma
Up to ~15% of cancers, tumor initiation attributed to infection1
![Page 7: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/7.jpg)
Sandler RS et al. New Engl. J. Med 2003;348:891-899
Anti-inflammatory drugs prevent tumor recurrence
Kaplan-Meier estimates of the time to a first adenoma in patients with previous colorectal cancer
![Page 8: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/8.jpg)
Macrophages in breast cancer
Leek RD et al., Cancer Res 1996;56:4625-4629 Steidl C et al., NEJM 2010;362:875-885
Macrophages in Hodgkin’s lymphoma
Influx of innate immune cells correlates with poor prognosis
![Page 9: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/9.jpg)
Pro-tumor
Anti-tumor
Immune system and cancer: A double-edged sword
![Page 10: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/10.jpg)
De Visser KE et al., Nat Rev. Cancer 2006;6:24-37
Impaired immune responses correlate with higher cancer incidence
![Page 11: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/11.jpg)
Galon J et al., Science 2006;313:1960-1964
High-density tumor-infiltrating lymphocytes (TILs) correlate with survival advantage in colorectal tumors
![Page 12: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/12.jpg)
Slide: Seth Coffelt
Part 1: Micro environmental regulation of tumor progression
Mechanisms
![Page 13: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/13.jpg)
Klemm F and Joyce JJ Trends in Cell Biology 2015; 25:198-213
1. Tumor vasculature
2. Cancer-associated fibroblasts
3. Inflammatory cells
4. Extracellular matrix
Major components of the tumor micro-environment
![Page 14: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/14.jpg)
Slide: Seth Coffelt
![Page 15: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/15.jpg)
Anti-tumor immunity
Cancer Growth
Chronic inflammation Tissue homeostasis
Controversial role of the immune system during cancer development
Pro-tumor
Anti-tumor
![Page 16: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/16.jpg)
Quail DF and Joyce JA, Nature Medicine 2013;19:1423-1437
Establishment of inflammatory tumor micro-environment “Wounds that never heal”
![Page 17: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/17.jpg)
Slide: Seth Coffelt
Macrophage infiltration in breast cancer
What have experimental studies taught us regarding the role
of the immune system during cancer development?
What models are available to study this?
![Page 18: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/18.jpg)
Lin E.Y. et al., J. Exp. Med. 2001;193:727-740
Macrophages enhance breast cancer metastasis formation
• MMTV-Polyoma virus Middle T (PyMT)-transgenic mice – PyMT expression under control of MMTV promoter in mammary epithelium – Spontaneous development of breast cancer
![Page 19: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/19.jpg)
Macrophages contribute to cancer progression
Lin E.Y. et al., J. Exp. Med. 2001;193:727-740
Reconstitute CSF1R in Macrophage-deficient mice
Tumor grade
![Page 20: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/20.jpg)
Macrophages contribute to cancer progression at multiple levels
Pollard J. W., Nat Rev Cancer 2004;4:71-78
(e.g. CSF-1, VEGF )
(e.g. VEGF)
(e.g. MMPs)
(e.g. EGF)
![Page 21: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/21.jpg)
Hagerling C. et al., Trends Cell Biol 2015;25:214-220
Conversion of (innate) immune cells during cancer progression
![Page 22: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/22.jpg)
Slide: Seth Coffelt
Part 2: The inflammatory tumor micro-environment and anti-cancer therapy
![Page 23: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/23.jpg)
Anti-cancer therapies targeting the tumor micro-environment
Quail DF and Joyce JA, Nature Medicine 2013;19:1423-1437
![Page 24: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/24.jpg)
Klemm F. and Joyce JA, Trends in Cell Biology 2015;25:198-213
How the TME can influence response to anti-cancer therapies
![Page 25: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/25.jpg)
Slide: Seth Coffelt
T cell infiltration in breast cancer
![Page 26: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/26.jpg)
(Cytotoxic) T cell-mediated tumor cell kill
MHC I
![Page 27: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/27.jpg)
Chen DS and Mellman I, Immunity 2013;39:1-10
The Cancer Immunity Cycle
![Page 28: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/28.jpg)
α-PD-1, α-CD137
Costimulation
Blocking coinhibition
Radio-immunotherapy promise:
Achieving SYSTEMIC synergism by combining LOCAL radiotherapy with immune-modulation
Radio-immunotherapy: Concept
Verbrugge I et al., Cancer Res 2012;72:3163-3174 Verbrugge I et al., Radiation Res 2014;82:219-229 Kroon P et al., Cancer Immunol Immunother 2016;65:753-763
![Page 29: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/29.jpg)
Small animal image-guided radiotherapy: mimicking clinical protocols
Movies: Jan-Jakob Sonke
![Page 30: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/30.jpg)
• Triple-negative breast cancer cell line
• Derived from MMTV-Polyoma virus Middle T (PyMT)-transgenic mouse
Transplantable AT-3 breast cancer model
(
Radiotherapy
Immunotherapy
![Page 31: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/31.jpg)
α-CD137
α-PD-1
Co-stimulation
Blocking Co-inhibition
Immunotherapy improves the response to radiotherapy
Verbrugge I et al., Cancer Res 2012;72:3163-3174
Control Immunotherapy
Radiotherapy Radio-immunotherapy
![Page 32: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/32.jpg)
Radiotherapy can improve immunotherapy responses to out-of-field tumor
Deng L et al., J Clin Invest 2014;124:687-695
Irradiated tumor Non-irradiated tumor
![Page 33: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/33.jpg)
α-PD-1, α-CD137
α-CD137
α-PD-1
(Chemo) Radio-immunotherapy to enhance tumor control
![Page 34: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/34.jpg)
Take home messages
Cancer development/progression:
• A pre-existing inflammatory environment can promote tumor initiation (‘seed and soil’) • Innate and adaptive immune cells within the TME are diverse, plastic, and in constant
dialogue with each other and the developing tumor • Upon loss of tissue homeostasis, tumor cells facilitate formation of an inflammatory TME
that can support a growing tumor
Response to therapy:
• TME can impair and enhance the efficacy of therapeutic interventions through pre-existing and therapy-induced mechanisms
• TME may be targeted (‘re-educated’) to halt tumor progression • Targeting the TME in combination with novel or conventional therapies (e.g. chemo-,
radiotherapy, immunotherapy) most likely required to eliminate tumors
Anti-tumor immunity
Cancer Growth
Chronic inflammation Tissue homeostasis
Pro-tumor
Anti-tumor
![Page 35: The inflammatory tumor micro-environment · 2018. 10. 9. · The inflammatory tumor micro-environment: a critical regulator of tumor development and therapy response Inge Verbrugge](https://reader033.vdocuments.net/reader033/viewer/2022053121/60a51af9be825806345eddcd/html5/thumbnails/35.jpg)
Juntendo University (Tokyo, Japan)
Hideo Yagita (antibodies)
Division of Tumor Biology and Immunology Paula Kroon Elselien Frijlink Andriy Volkov Irene vd Haar-Avila Victoria Iglesias-Guimarais Seth Coffelt Karin de Visser Blank group Jules Gadiot Marcel Deken Jannie Borst
Department of Radiotherapy Artem Khmelinskii Marcel Verheij
NKI core facilities
Acknowledgements