P4-09-19: PCNA+ Tumor Associated Macrophages Are Associated with M1 and M2 Gene Expression, and Confer Poor Prognosis in the Absence of Anti-Tumor Immune Environment.

Abstract

Abstract Background Tumor associated macrophages (TAMs) promote breast tumor progression through the production of angiogenic factors, stromal breakdown factors, and the suppression of adaptive immunity. TAMs are recruited from the circulation to the tumor site, and can undergo a spectrum of phenotypic changes, with two contrasting activation states described in the literature: the M1 anti-tumoral and M2 pro-tumoral phenotypes. We previously identified a population of PCNA+ TAMs associated with high grade, hormone receptor (HR) negative tumors with poor outcomes. We hypothesized that high PCNA+ TAMs would be associated with expression of M2 related genes. Methods We used immunohistochemistry to measure PCNA+ TAM levels (double positive for PCNA and CD68) in 135 invasive breast cancer cases from the I-SPY 1 Trial, a prospective neoadjuvant trial with serial core biopsies and gene array data. We developed gene-sets representing M1 related, M2 related, and anti-tumoral immune response (represented by cytotoxic T cells and MHC Class II) genes based on literature review. We compared PCNA+ TAM levels, expression of these gene-sets, and outcomes. Results Higher than mean PCNA+ TAM counts were associated with increasing grade (p < 0.001), HR negativity (p < 0.001), and decreased recurrence free survival (RFS, p = 0.05). Among subjects who had a pathologic complete response (pCR), there was no difference in RFS between those with high versus low PCNA+ TAMs. Among subjects without pCR, those with high PCNA+ TAMs had significantly worse RFS than those with low PCNA+ TAMs (p = 0.0028). In the 95 subjects with both PCNA+ TAM results and gene expression arrays available, high PCNA+ TAM levels were associated with more M1 than M2 related genes. The gene-set representing anti-tumoral immune environment was not by itself associated with RFS. However, those subjects with both high PCNA+ TAMs and the absence of anti-tumoral immune response gene expression had significantly worse RFS than those with high PCNA+ TAMs but the presence of anti-tumoral immune related genes (p = 0.01). Conclusions High PCNA+ TAMs had different effects on outcomes depending on tumoral immune environment. Instead of being purely M2 macrophages, PCNA+ TAMs likely represent a heterogeneous mixture of TAMs with different polarization states. Additional markers are needed to distinguish anti-tumoral from pro-tumoral PCNA+ TAMs. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-19.