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

Slide: Seth Coffelt

Slide: Seth Coffelt

Part 1: Micro environmental regulation of tumor progression

Clinical Associations

Rudolf Virchow (1821-1902) German Pathologist

1863: First hypothesis linking inflammation and cancer development

Image: Seth Coffelt

Inflammatory tumor micro-environment in human invasive breast cancer

Question:

Can inflammation lead to cancer? Do you have examples?

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

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

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

Pro-tumor

Anti-tumor

Immune system and cancer: A double-edged sword

De Visser KE et al., Nat Rev. Cancer 2006;6:24-37

Impaired immune responses correlate with higher cancer incidence

Galon J et al., Science 2006;313:1960-1964

High-density tumor-infiltrating lymphocytes (TILs) correlate with survival advantage in colorectal tumors

Slide: Seth Coffelt

Part 1: Micro environmental regulation of tumor progression

Mechanisms

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

Slide: Seth Coffelt

Anti-tumor immunity

Cancer Growth

Chronic inflammation Tissue homeostasis

Controversial role of the immune system during cancer development

Pro-tumor

Anti-tumor

Quail DF and Joyce JA, Nature Medicine 2013;19:1423-1437

Establishment of inflammatory tumor micro-environment “Wounds that never heal”

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?

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

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

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)

Hagerling C. et al., Trends Cell Biol 2015;25:214-220

Conversion of (innate) immune cells during cancer progression

Slide: Seth Coffelt

Part 2: The inflammatory tumor micro-environment and anti-cancer therapy

Anti-cancer therapies targeting the tumor micro-environment

Quail DF and Joyce JA, Nature Medicine 2013;19:1423-1437

Klemm F. and Joyce JA, Trends in Cell Biology 2015;25:198-213

How the TME can influence response to anti-cancer therapies

Slide: Seth Coffelt

T cell infiltration in breast cancer

(Cytotoxic) T cell-mediated tumor cell kill

MHC I

Chen DS and Mellman I, Immunity 2013;39:1-10

The Cancer Immunity Cycle

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

Small animal image-guided radiotherapy: mimicking clinical protocols

Movies: Jan-Jakob Sonke

• Triple-negative breast cancer cell line

• Derived from MMTV-Polyoma virus Middle T (PyMT)-transgenic mouse

Transplantable AT-3 breast cancer model

(

Radiotherapy

Immunotherapy

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

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

α-PD-1, α-CD137

α-CD137

α-PD-1

(Chemo) Radio-immunotherapy to enhance tumor control

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

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