Tumor vascularity in ovarian cancer

In ovarian cancer, it has become increasingly clear that tumor-infiltrating lymphocytes (TILs) confer a survival benefit to patients. 1 It is tempting to strive to further define the key TIL subsets driving antitumor immunity, as one can envision developing T cell-based therapy armed with this knowledge. Indeed, refinements in adoptive T-cell therapy seeking to identify antigen-specific populations are currently under intense investigation in melanoma studies. Given the immuno-suppressive tumor environment, one must question how TILs perform their antican-cer role under these hostile conditions. Generally, hypoxia is a common feature of tumors and low oxygen can attenuate immune responses due to the corresponding signaling events and metabolic changes initiated by T cells in hypoxic environments. 2 In ovarian cancer, hypoxia has been observed to promote regulatory T cell (Treg) recruitment and alter CD4 + T cell differentiation through degradation of the T-cell fate regulatory transcription factor FoxP3 and resultant promotion of T helper type-17 (Th17) development. 3,4 Conversely, other studies have shown that hypoxia can promote the expression of FoxP3 in CD4 + T cells. 5 Regardless, metabolically , it is well established that low oxygen in tumors stabilizes the hypoxia inducible factor-1α (HIF-1α), which in turn reprograms the entire metabolic network of tumors. 6 In response, hypoxic tumors increase the production of lactate that promotes the recruitment of myeloid-derived suppressor cells (MDSCs) which have a variety of immunosuppressive properties. For example, a high concentration of lactate has been observed to inhibit cytotoxic T-cell activation and causes a shift toward a Th17/23 cell phenotype. 7 Our recent study has shown that T-cell infiltration and antitumor function is dependent upon the degree of tumor vas-culature and corresponding oxygenation. 8 Using 2 established markers of tissue vascularization and oxygenation, CD31, to mark blood vessel endothelial cells and vascular endothelial growth factor (VEGF), a hypoxia-inducible gene, we assessed the influence of hypoxia on TILs. 8 Our initial analysis revealed that, compared with CD31 negative tumors (hypoxic), CD31 positive tumors (vas-cularized and normoxic) correlate with better disease-specific patient survival. Albeit counterintuitive, we posited that the increase in survival was related to lym-phocyte infiltration into the tumor. When a series of tumor sections from the tissue array were histologically assessed for the presence of T cell markers (CD8, CD4, and FoxP3), we found that the expression of each marker had a strong positive correlation with CD31 expression. Further characterization using cytotoxicity markers (TIA-1 and granzyme B) …