Effects of oxygen on the antigenic landscape of prostate cancer cells: Is there a way to clinical utility of manipulating oxygen tension in cancer?: Beyond the Abstract
Manipulating oxygen levels in tumors and immune cells elicits tumor immunity: Tumor cells cultured at 5 percent O2, the oxygen tension akin to that found in tumors, increased their efficacy as tumor-specific vaccines in a murine model (4). When dendritic cells presented the antigens from lysed primary tumor cells cultured at 5 percent O2, the resulting cytolytic T cells killed tumor cells more effectively than those elicited by dendritic cells presenting antigens from cells cultured in air (20 percent O2; ref. (5).
Recently, we assessed the effect of hypoxia on antigen expression in prostate cancer (PCa) cell lines (6). We screened PCa patient plasma serologically and used two-dimensional gel electrophoresis to identify the autoantibodies binding to antigens expressed by PCa cells. We found that hypoxia enhanced binding of molecules in PCa patient plasma to PCa cell lysates. Some of the identified, hypoxia-reactive, tumor-associated antigens hold potential as tumor markers in PCa tissues. Alongside with validating the relevance of tumor-associated hypoxia in PCa immune-reactivity, our findings provide support to the value of hypoxia as a tool in the development of markers and immunotherapeutic targets for PCa.
While our findings help define the relationship of antigen expression and oxygen tension in tumors and their microenvironments, they do not prove that this relationship is relevant in vivo. This is a limitation of our study and impetus for future work. Others have found endothelial growth factor VEGF as a major player in suppressing immunity (7). Developing cancer cell lines for the use as therapeutic vaccines, we found that hypoxia stimulated secretion of VEGF in cultured PCa (6) and ovarian carcinoma cells (CRG and SV-P, unpublished data) suggesting that the effects of hypoxia are not peculiar just to PCa. From that perspective, manipulation of oxygen tension to help rebuilding immunity in cancer patients could be considered for different types of cancer.
There are several questions pertinent to the further progress in understanding the tumor-hypoxia realm: First, what is the crux of the oxygen-tension effect in tumors: steady-state hypoxia or time-dependent changes of oxygen tension? Second, if we could manipulate oxygen tension in tumors and their environments, would that meaningfully contribute to therapy? Finally, by what means can we do that? While there are hints to the answers to these questions, none has been definitively answered.
It is tempting to speculate (and is compatible with the honored principles of physiological regulation) that time-dependent changes of oxygen tension play a role in (tumor) cells. In a set of preliminary experiments, we compared the levels of hypoxia-inducible factor 1- (HIF-1) in human ovarian cancer cells cultured in air, and under hypoxic (5% O2) and hyperoxic (>95% O2) conditions. While expectedly hypoxia increased the levels of HIF-1α and the VEGF release rate compared to normoxic cells, hyperoxic cells also expressed more HIF-1α and VEGF (CRG and SV-P, unpublished data). These results allude to the possibility that perturbation in oxygen tension, rather than its low steady-state levels, may be sufficient to trigger the cellular responses. How the direction and duration of the change of oxygen tension affect the complexity of interactions of the tumor and the microenvironment is a matter of future research. Currently, the only oxygen—tension-modulating therapy is application of hyperbaric oxygen. However, its role and effects in tumors have not been established (8), partly because the early empirical approaches failed and discouraged studies that, today, could be aided by mechanistic insights achievable by contemporary analytical and system-biology methods.
Written by: 1-3Christian R. Gomez and 4Stanimir Vuk-Pavlović
1 Cancer Institute, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216 USA
2 Department of Pathology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216 USA
3 Department of Radiation Oncology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216 USA
4 Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 USA
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