A Pro-Inflammatory Tumor Microenvironment with High Chemokine Expression and High Tumor-Infiltrating CD3+CD8+ Numbers Associates with Improved Survival in Ewing Sarcoma (EWS)
D Berghuis, SJ Santos, JJ Baelde, AHM Taminiau, RM Egeler, MW Schilham, PCW Hogendoorn, AC Lankester. Leiden University Medical Center, Leiden, Netherlands
Background: Despite multimodal therapy, patients with advanced-stage EWS have a poor prognosis. Immunotherapeutic strategies may provide novel treatment modalities. Although EWS cells can be recognized and targeted by T and NK cells in vitro, limited information is available about tumor-immune interactions within the tumor microenvironment. Here we investigate characteristics of the immune cell infiltrate and chemokine expression in EWS, as well as their mutual relationship and correlations with clinicopathological parameters.
Design: EWS tumors (n=20) were evaluated by quadruple immunohistochemistry for presence and spatial distribution of tumor-infiltrating lymphocytes (TIL; CD3+/CD4+/CD8+). Chemokine expression was analyzed in both tumors and cell lines (n=9) by qRT-PCR, immunohistochemistry and flow cytometry.
Results: Substantial inter-tumor variations were observed for both numbers and distribution (tumor- or stroma-infiltrating) of TIL as well as for chemokine expression profiles. Tumor-infiltrating T-cells contained higher percentages of CD3+CD8+ cells as compared to stroma-infiltrating cells (p=0.04). Moreover, survival analysis revealed prognostic benefit of a more robust CD3+CD8+ T-lymphocytic infiltrate (p=0.04). Positive correlations between gene expression levels of several functionally related, pro-inflammatory chemokines (mainly CCR5-/ CXCR3-ligands) and TIL numbers (p<0.05) suggested that expression of these chemokines contributed to TIL recruitment. The presence of both constitutive and IFNγ-inducible expression of several pro-inflammatory chemokines (CCL5, CXCL9, CXCL10) was confirmed at protein level. High chemokine expression levels, like the presence of high tumor-infiltrating CD3+CD8+ cell numbers, associated with improved overall survival (p=0.03).
Conclusions: These results demonstrate prognostic benefit of a tumor microenvironment with high levels of pro-inflammatory chemokines as well as high numbers of tumor-infiltrating CD3+CD8+ T-lymphocytes and point to a role for adaptive anti-tumor immune responses in prevention of tumor progression.
Category: Bone & Soft Tissue
Tuesday, March 23, 2010 9:30 AM
Poster Session III # 25, Tuesday Morning