Photodynamic Therapy Mechanisms of Anti-tumor Immunity PDF Download

Author: Edith Njeri Kabingu
Publisher:
ISBN: 9780542999611
Category :
Languages : en
Pages : 148

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Book Description
Most cancer patients get standard therapies such as chemotherapy and radiation to treat their disease. These therapies are however mainly efficient in targeting the primary tumor and not metastatic disease. Immunotherapeutic strategies to target both primary and disseminated disease have been explored over the years. Photodynamic therapy (PDT) has been explored as a way to target the host's immune defenses to eradicate tumors. PDT is an established therapy for the treatment of various types of cancer. It uses a combination of light and photosensitizing drugs to induce damage to tumor tissue. Pre-clinical and clinical studies have shown that tumor control by PDT correlates with induction of anti-tumor immunity and suggest that the enhanced anti-tumor response may be effective against distant tumors. We have tested this hypothesis by measuring the ability of tumor bearing mice treated with PDT to control tumors outside the local treatment field. Two models were used to address this hypothesis. An experimental metastases model (EMT6) and a spontaneous metastases model (4T1). Using the experimental metastases model we have shown that in situ PDT of subcutaneous tumors of mice bearing both subcutaneous EMT6 mammary tumors and lung tumors results in a significant reduction in the number of lung tumors (an average of 6.5 +/- 3.9 tumors/lung) compared to mice whose subcutaneous tumors were surgically removed (an average of 41.2 +/- 8.5 tumors/lung). This control of tumors outside the field of treatment depended on treatment of tumors in the field because treatment of tumor free areas in tumor bearing mice did not result in control of tumors outside the treatment field. Furthermore, the ability to control these tumors depended upon CD8+ cells and appeared to be independent of CD4+ cells, as tumor control was maintained in mice depleted of CD4 expressing cells and SCID mice receiving CD8+ cells alone prior to PDT were able to control the growth of tumors outside the treatment field. In addition, the memory response did not appear to require CD4 + T cells since SCID mice inoculated with CD8+ were tumor free when challenged with EMT6 tumors 40 days after PDT treatment of primary EMT6 tumors. The mechanism by which this CD8+ T cell response may happen without CD4+ T cell help may be driven by NK cells because NK depleted SCID mice that were reconstituted with CD8 + T cells could not control distant EMT6 tumors following local PDT whereas those not depleted of NK cells but reconstituted with CD8+ T cells could. However the spontaneous metastases 4T1 model did not give us the same kind of results. The 4T1 model proved difficult to treat with PDT. There was no significant change in the number of spontaneous lung metastases after PDT of the primary tumor. A comparative study to investigate differences in PDT responses of 4T1 tumors compared to EMT6 tumors revealed that there may be immune suppression by regulatory T cells in 4T1 tumors. IL-6 production also appears to be enhanced after PDT of 4T1 tumors compared to EMT6 tumors (over 3 fold higher at the 8h time point). This could be driving proliferation and survival of 4T1 tumors. The expression of Bcl-2 in 4T1 and not EMT6 tumors and Bax in EMT6 and not 4T1 tumors supports the possibility that 4T1 tumors are protected from death and hence their inability to be killed by PDT. These studies suggest that in some tumors, PDT can be a potential immunotherapeutic strategy for controlling distant disease through induction of a specific host anti-tumor immune response mediated by CD8+ T cells. PDT may however not work for all tumors, but understanding differences in the response of various tumors may contribute to the development of strategies to overcome suppressive mechanisms.