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652 Chemokine CCL21 induces an immunotolerant tumour microenvironment leading to poorer survival in ovarian cancer
  1. Elaine Yl Leung1,2,
  2. Dimitris Athineos3,
  3. Sarwah Koutaiba Al-Khalidi3,
  4. John Cole1,
  5. Kieran Woolcock1,
  6. Marieke Pingen1,
  7. Robin Bartolini1,
  8. Laura Medina-Ruiz1,
  9. Paul Burgoyne1,4,
  10. Gareth Bryson5,
  11. Rory Canning6,
  12. Colin Nixon3,
  13. Catherine Hughes1,
  14. Richard Hohne1,
  15. Seth Coffelt1,3,
  16. Darren Ennis7,
  17. Karen Blyth3,
  18. Iain Mcneish7,
  19. Ed Roberts8 and
  20. Gerard Graham1
  1. 1University of Glasgow, Glasgow, UK
  2. 2University of Birmingham, Birmingham, UK
  3. 3CRUK Scotland Institute, Glasgow, UK
  4. 4Scottish National Blood Transfusion Service, Edinburgh, UK
  5. 5Queen Elizabeth University Hospital, Glasgow, UK
  6. 6University Hospital Crosshouse, Glasgow, UK
  7. 7Imperial College, London, UK
  8. 8CRUK Scotland Centre, Glasgow, UK


Introduction/Background Malignant ascites is a hallmark of advance ovarian cancer (OC) and an accessible resource to evaluate OC immune microenvironment. Previous studies on ascites chemokines have not explored the mechanistic role of soluble CCL21 in OC. Here, we evaluated the landscape of soluble chemokines and cytokines in ascites.

Methodology Cell-free human ascites supernatants from 53 patients were analysed for chemokine expression using multiplex immunoassays. Two tumour microarrays (TMAs) from additional independent patient cohorts (n=92) were evaluated by immunohistochemistry for chemokine expression and immune cell infiltration. To evaluate the mechanistic importance of CCL21 in OC, a novel transplantable murine model (ID8 Trp53-/- OVA-CCL21high) with Trp53 aberration (representative of high-grade serous OC) and high expression of CCL21. In vivo influence of CCL21 was evaluated by survival, flow cytometry and RNA-sequencing.

Results High CCL21 was associated with poorer patient survival (HR=2.40, 95%CI= 1.13–5.12, p=0.013; figure 1), and preferentially expressed by tumours and metastases. Our novel murine model confirmed the mechanistic importance of CCL21 on survival- the median survival was 57.5 days in the CCL21-high group, compared to 97 days in the controls (HR 5.38, 95%CI 1.48–19.6, p<0.0001).

However, CCL21 did not directly promote malignant cell growth and invasion, suggesting it exerts its detrimental effects via the tumour microenvironment. Further evaluations revealed a less inflammatory tumour microenvironment, a reduction of ascites dendritc cells (crucial for antigen presentation; 18.9% versus 36.9%, p=0.036) and CD44+ T cells (related to memory T-cells associated with impaired antigen presentation; median fluorescence index- 2072 versus 5062 for CCL21-high and control, respectively; p=0.020).

Conclusion Our results confirmed CCL21 led to poorer survival in OC, and was associated with an immunosuppressive tumour microenvironment, disrupted leukocyte migration, reduction in tumour-associated dendritic cells and immunotolerant tumoural T-cell phenotypes. The use of novel strategies, such as dendritic vaccines, to promote anti-tumoural responses warrants further investigations in ovarian cancer.

Disclosures None

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