The inflammatory tumor micro-environment: A critical regulator of - - PowerPoint PPT Presentation

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The inflammatory tumor micro-environment: A critical regulator of - - PowerPoint PPT Presentation

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The inflammatory tumor micro-environment: A critical regulator of cancer progression, metastasis and response to (radio-immuno)therapy Inge Verbrugge, Ph.D. Division of Immunology, NKI-AvL Rotterdam, October 24 2017 Slide: Seth Coffelt Major

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The inflammatory tumor micro-environment:

A critical regulator of cancer progression, metastasis and response to (radio-immuno)therapy

Inge Verbrugge, Ph.D. Division of Immunology, NKI-AvL

Rotterdam, October 24 2017

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Slide: Seth Coffelt

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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

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Rudolf Virchow (1821-1902) German Pathologist

1863: First hypothesis linking inflammation and cancer development

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Inflammatory tumor micro-environment in human invasive breast cancer

Image: Seth Coffelt

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Slide: Seth Coffelt

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Immune system and cancer: A double-edged sword Pro-tumor Anti-tumor

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Slide: Seth Coffelt

Chronic inflammation can promote tumorigenesis

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Sandler RS et al. New Engl. J. Med 2003;348:891-899

Anti-inflammatory drugs prevent tumor recurrence

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Influx of innate immune cells correlates with poor prognosis

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

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Immune system and cancer: A double-edged sword Pro-tumor Anti-tumor

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Impaired immune responses correlates with high cancer incidence

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

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High-density TILs correlate with survival advantage in colorectal tumors

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

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Paradoxical roles of the immune system during cancer development

Slide: Seth Coffelt

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Cancer cells must evade anti-tumor immune response

Chen and Mellman Immunity 2013;39:1-10

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Cancer immunoediting: from immunosurveillance to escape

Strausberg RL et al., Genome Biol. 2005;6:211

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

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

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Controversial role of the immune system during cancer development What have experimental studies taught us regarding the role of the immune system during cancer development? Anti-tumor immunity Cancer Growth Chronic inflammation Tissue homeostasis

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  • Cancer development/progression
  • Metastasis formation
  • Response to therapy

Inflammatory tumor micro-environment

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  • Cancer development/progression
  • Metastasis formation
  • Response to therapy

Inflammatory tumor micro-environment

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Macrophage infiltration in breast cancer

Slide: Seth Coffelt

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Macrophages contribute to cancer progression

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

Conversion innate immune cells during tumor development

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  • Cancer development/progression
  • Metastasis formation
  • Response to therapy

Inflammatory tumor micro-environment

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  • In 1889, Paget noticed that metastasis was more frequent in

certain organs and proposed it was not random

  • Metastasis results from signaling between cancer cell (seed)

and organ microenvironment at metastatic sites (soil) Seed-and-Soil Hypothesis “When a plant goes to seed, it seeds are carried in all directions; but they can only live and grow if they fall

  • n congenial soil.”
  • Stephen Paget, 1889

Paget S. Cancer Metastasis Rev. 1989;8:98-101 Lanley RR et al., Int J Cancer 2011;128;2527-2535

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Macrophages enhance breast cancer metastasis formation

Lin E.Y. et al., J. Exp. Med 2001;193:727-740

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Immune cell infiltration in breast cancer

Slide: Seth Coffelt

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Neutrophils enhance breast cancer metastasis formation

Coffelt SB et al., Nature 2015;522:345-348

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γδ T cell-IL17-neutrophil axis promotes metastatic breast cancer

Coffelt SB et al., Nature 2015;522:345-348

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  • Cancer development/progression
  • Metastasis formation
  • Response to therapy

Inflammatory tumor micro-environment

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Klemm F. and Joyce JJ (2015) Trends in Cell Biology 25: 198-213

Intrinsic or acquired contributions of the TME to therapy response

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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

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Hooijkaas A et al., Am J Pathol;181:785-794

  • Tyr::CreERT2;PtenloxP/loxP;BRAFCA/+ transgenic mice

– Tamoxifen administration to the skin  PTEN loss, expression of mutant BRAF in melanocytes – Driver lesions representative of melanoma, mutational load is NOT

Radio-immunotherapy in GEMM (melanoma)

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  • Radiotherapy + α-CD137 / α-PD-1 mAbs delays tumor outgrowth

– Targeting α-CTLA-4/α-PD-1, IL-2, CD27 not effective Control Radiotherapy Tumor doubling time (days)

Efficacy of radio-immunotherapy in spontaneous melanoma?

Kroon P et al., Cancer Immunol Immunother 2016;65:753-763

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T cell infiltration in TME following radio-immunotherapy

Kroon P et al., Cancer Immunol Immunother 2016;65:753-763

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α-PD-1, α-CD137

α-CD137 α-PD-1

Radio-immunotherapy enhances local tumor control

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Cancer therapy: kill tumor cells AND tip the balance in the TME in favor of anti-tumor immunity Anti-tumor immunity Cancer Growth Chronic inflammation Tissue homeostasis

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  • Cancer development/progression

– Upon loss of tissue homeostasis, tumor cells facilitate formation of inflammatory TME that supports tumor development/progression

  • Metastasis formation

– Inflammation provides ‘soil’ at pre-metastatic niches for cancer cells ‘seeds’ to disseminate and grow

  • Response to therapy

– Curative therapy may require tumor cell kill AND attenuation of TME to favor tissue homeostasis/anti-tumor immunity

Conclusion/discussion

Highly dependent on e.g. genetic make-up, cell of origin and location of tumor, (immune) status of patients, requires personalized (therapy) approaches!

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Juntendo University (Tokyo, Japan) Hideo Yagita (antibodies) Division of Tumor Biology and Immunology Paula Kroon Elselien Frijlink Victoria Iglesias Seth Coffelt Karin de Visser Blank group Jules Gadiot Marcel Deken De Visser group Jannie Borst Department of Radiotherapy Artem Khmelinskii Marcel Verheij NKI core facilities

Acknowledgements