The Indoleamine 2,3-Dioxygenase (IDO) Pathway Is Constitutively Activated in HPV-Mediated Oropharyngeal Carcinoma
Jie Xu, Tatyana Isayeva, Michael Saag, Margaret Brandwein-Gensler. University of Alabama at Birmingham, Birmingham, AL
Background: Overall cancer-specific immunity is impacted by the degree of immune tolerance mediated by both cancer and HPV, balanced against the degree of successful local adaptive immunity. Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme which promotes immune tolerance. IDO activation in dendritic cells results in CD8+ apoptosis and differentiation of naïve CD4+ into Treg, thus down-regulating adaptive immunity. The IDO pathway has not yet been investigated in the context of HPV-mediated oropharyngeal cancer (OPC). The rationale for this stems from the fact that there are a number of constitutive HPV-mediated pathways which promote immune dysregulation. We investigate the IDO pathway in head and neck cancer cell lines and OPC with known HPV status.
Design: We studied 8 cancer cell lines from the head and neck: 1HPV16+ OPC cell line and 7 HPV-negative cell lines. Two of these HPV-negative cell lines were transfected with HPV16 E6/E7 vectors. IDO mRNA was measured by RT-PCR; activated GCN2 (a downstream IDO target) was measured by Western blot. We also studied 31 OPC specimens for IDO protein by IHC; the HPV16/18 status was previously established by nested RT-PCR for type-specific E6 and E7 transcripts.
Results: Constitutive IDO and GCN2 activation was present only in the HPV16+ OPC cell line, but not in any HPV-negative cell lines. Both HPV transfected cell lines demonstrated new IDO and GCN2 activation.
In the OPC cohort, 15/31 tumors (48%) were HPV16/18 positive. IDO tumor expression was seen in 93% (13/14) of HPV16+OPC, and 17% (3/17) of HPV-negative OPC. Tumor IDO expression was significantly associated with HPV-mediated OPC (p < 0.001).
Conclusions: These data support the idea that the IDO pathway is constituitively activated in HPV-mediated OPC. Thus IDO activation is yet another potential promoter of immune tolerance impacting the overall balance of local cancer immunity.
Category: Head & Neck
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 197, Monday Morning