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The impact of cellular senescence and DNA damage on colorectal tumour progression
  1. Helen K Angell1,2,3,
  2. Marie Tosolini1,2,3,
  3. Bernhard Mlecnik1,2,3,
  4. Gabriela Bindea1,2,3,
  5. Tessa Fredriksen1,2,3,
  6. Lucie Lafontaine1,2,3,
  7. Maximilian Waldner1,3,4,
  8. Franck Pagès1,3,5,
  9. Viia Valge-Archer6 and
  10. Jérôme Galon1,2,3
  1. Aff1 grid.503414.7Laboratory of Integrative Cancer Immunology INSERM U872 Paris France
  2. Aff2 grid.10992.330000000121880914Université Paris Descartes Paris France
  3. Aff3 grid.5805.80000000119553500Cordeliers Research CentreUniversité Pierre et Marie Curie Paris 6 Paris France
  4. Aff4 grid.5330.50000 0001 2107 3311University of Erlangen-NurembergErlangen Germany
  5. Aff5 grid.414093.bImmunologyGeorges Pompidou European Hospital Paris France
  6. Aff6 grid.417815.e0000000104335842MedImmune Ltd Cambridge UK

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Meeting abstracts

We have previously defined the immune contexture as the type, density, location and functional orientation of tumour infiltrating immune cells, associated with patient prognosis in colorectal cancer (CRC). Here we describe potential mechanisms, including the DNA damage response (DDR) and cellular senescence, as contributing factors in shaping this intra-tumoural immune reaction. Cellular senescence, permanent proliferation arrest, is triggered by exogenous or endogenous stress, including telomere shortening, DNA-damage or oncogene activation. We have evaluated the expression of 53BP1, pATM and p16INK4a in a cohort of 205 CRC patients. In addition, telomere length and senescence-associated β-galactosidase have been analysed. A large panel of immune markers, including CD3, CD45RO, CD8 and CD57, were evaluated immunohistochemically. Patients who had increased DDR and senescence correlated with improved prognosis, both disease free and overall survival. Patients with high 53BP1 and pATM had significantly higher numbers of infiltrating immune cells at both the tumour centre and invasive margin. Functional experiments, including a transwell chemotaxis system, have illustrated that immune cells migrate towards soluble factors produced by senescent tumour cells. Our data provide further mechanisms resulting in changes of specific immune cell densities within the tumour, illustrating links between senescence and aspects of the DDR with the control of the anti-tumour immune response, and thus CRC disease progression.