IB-11 * PSEUDO-PROGRESSION (PsdPg) IS A HARBINGER OF A MORE EFFECTIVE ANTI-TUMOR RESPONSE

Abstract

BACKGROUND: PsdPg is the increased contrast enhancement, high choline/creatine ratio and increased perfusion observed in the residual tumor bed of high-grade glioma patients after completion of temozolomide/radiation. It resolves within 3-6 months and incidence ranges from 10-31%. Though correlated with longer patient survival, its pathological basis is unclear. We used a cytokine/chemokine focused approach to compare the tumor microenvironment in pre- and post-treatment tumor tissue from patients with PsdPg to patients with true progression (TP). METHOD(S): We obtained pre-treatment formalin fixed paraffin embedded (FFPE) tissue from 35 GBM patients and post-treatment FFPE tissue from five patients with PsdPg and TP. A quantitative PCR array and custom Quantigene 2.0 multiplex was used to quantify gene expression corresponding to major cytokines/che-mokines. An 18-gene signature was used to determine the macrophage polarization score (cumulative M2-associated cytokine expression - cumulative Ml-associated cytokine expression). Immunohistochemistry (IHC) was used to confirm significantly different targets at the protein level. RESULT(S): IHC revealed 7-fold higher B-cell infiltration in TP patients as compared to patients with PsdPg (p = 0.003). Macrophage and T-cell infiltration were not significantly different between the two groups. Nevertheless, the cytokines associated with macrophage polarization indicated pro-tumorigenic (M2) polarization in TP patients while PsdPg patients exhibited classical anti-tumorigenic (M1) polarization. TP patients had a 10-fold higher M2 score (p = 0.03) compared to PsdPg patients. The M1 score of tissue from PsdPg patients post-treatment was 25-fold higher than their pre-treatment tissue (p = 0.01). Analysis of a 7-gene signature associated with natural killer (NK) cell recruitment and activation showed a 8-fold higher expression in pre-treatment tissue from PsdPg patients compared to TP patients (p = 0.009) suggesting that NK cells, which are mediators of anti-tumor immunity, play an important role in pseudo-progression. CONCLUSION(S): These data suggest a more effective anti-tumor immune response in PsdPg patients, which may explain their longer overall survival.