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Control of T cell infiltration and tumor rejection by regulatory T cells, basophils and macrophages

Sektioglu, Ibrahim Murathan

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Abstract

Most solid tumors are intrinsically resistant to immune rejection due to immunosuppressive mechanisms operative within the tumor microenvironment. Cancer patients frequently harbor elevated numbers of regulatory T cells (Tregs), which inhibit efficient anti-tumor T cell responses. We employed different mouse models for Treg depletion in order to study the mechanisms that control tumor rejection. Depletion of about 99% Tregs in Foxp3DTR knock-in mice resulted in complete rejection of transplanted HCmel 1274 and B16 melanomas in a CD8+ T cell-dependent way. In contrast, about 90% Treg depletion in BAC transgenic Foxp3.LuciDTR4 mice failed to induce complete rejection of HCmel 1274 and B16, demonstrating that low numbers of Tregs were able to control CD8+ T cell responses against the tumor. Treg depletion provoked drastic changes within tumor microenvironment, such as cytokine storm and strong infiltration of CD8+ T cells. In addition, substantial infiltration of basophils was observed. This study reported for the first time that tumor-associated basophils play a crucial role in tumor rejection. These intratumoral basophils produced large amounts of chemokines such as CCL3 and CCL4 that were found to be responsible fo the infiltration of tumor-specific CD8+ T cells into the tumor. IFN-γ produced by these CD8+ T cells resulted in skewing of tumor-associated macrophages from a M2-like phenotype to a M1-like phenotype. In a feedback mechanism, the M1-like macrophages potentiated infiltration of CD8+ T cells by secreting potent CD8+ T cell chemoattractants, including CCL2, CXCL9 and CXCL10, and by inducing normalization of the tumor vasculature.

The mechanisms of tumor rejection were also investigated in a second tumor model. Rip1-Tag5 (RT5) mice develop spontaneously pancreatic cancer, which precisely reflects the clinical development of pancreatic neuroendocrine tumors. Like almost all human and rodent tumors, these insulinomas contain an abnormal tumor vasculature, which acts as a barrier for T cell migration into the tumor. Thus, treatment of Rip1-Tag5 mice with adoptively transferred T cells failed to eradicate the tumors. However, when T cell transfer was combined with CpG-ODN as an inducer of pro-inflammatory signals, upregulation of T cell adhesion molecules such as VCAM-1 on the tumor endothelium was observed, as well as strong infiltration of T cells, prolonged survival of tumor-bearing mice. Of note, CpG-ODN was found to bind to CD206+ iNOS- M2-like macrophages and to polarize them into CD206- iNOS+ M1-like macrophages. Depletion of macrophages and blockade of iNOS revealed that the iNOS activity by the M1-skewed tumor macrophages was responsible for the increased VCAM-1 expression on the tumor endothelium and for the subsequent T cell infiltration and tumor rejection. Notably, transfer of pre-activated iNOS+ macrophages in combination with tumor-specific CD8+ T cells, in the absence of additional CpG-ODN, was also able to promote VCAM-1 expression and T cell infiltration. In contrast, iNOS-deficient macrophages failed to do so, highlighting the critical role of NO production by M1-polarized tumor macrophages. In vitro, incubation of human endothelial cells with iNOS-expressing human macrophages or with the NO donor GTN induced expression of adhesion molecules, such as VCAM-1, ICAM-1 and E-selectin, but only with low doses of GTN, whereas higher doses resulted in inhibition. Thus, these results indicate that NO production by M1-polarized tumor macrophages is a critical step in tumor therapy.

Together, the data from both mouse models show that adoptive T cell therapy and basophil/macrophage targeting strategies, or co-transfer of M1-polarized macrophages are able to evoke efficient T cell infiltration and tumor rejection. These findings have implications for immunotherapeutic interventions in cancer patients.

Item Type: Dissertation
Supervisor: Hämmerling, Prof. Dr. Günter J.
Place of Publication: Heidelberg
Date of thesis defense: 16 July 2015
Date Deposited: 27 Jul 2015 07:36
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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