Title

Modulation of BMPR1α Function for Cancer Immunotherapy

Presenting Author Name/s

Zuri Jules-Culver

Faculty Advisor

Piotr Kraj

Presentation Type

Poster

Disciplines

Cancer Biology | Immunity

Description/Abstract

Despite increased understanding of how the transforming growth factor-β (TGF-β) regulates T cell functions, the immunomodulatory roles of other members of the TGF-β cytokine family, especially bone morphogenetic proteins, remain largely unknown. We have found that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3) expressed by activated effector and regulatory CD4+ T cells, modulates functions of both of these cell types by promoting generation of adaptive TR and inhibiting generation of Th17 cells from naive CD4+ T cells. Mice where BMPR1α is deleted in T cells (BMPR1αT- mice) had a decreased proportion of thymic derived TR cells. Activation of BMPR1α deficient (BMPR1α-) CD4+ T cells leads to generation of Th1/Th17-like effector cells expressing high levels of inflammatory cytokines, including IFN-γ, IL-17 and TNF family proteins. Immunization of BMPR1αT- mice induced vigorous inflammatory response and mice were able to better control B16 melanoma tumors. Tumor infiltrate had very few TR cells and higher proportion of CD8+ T cells compared to tumors in wild type mice. These data demonstrate that TGF-β mediated immunosuppression in the course of tumor growth can be bypassed by inhibition of BMPR1α signaling.

Transcriptome analysis of wild type and BMPR1α- CD4+ Th cells revealed differential expression of transcription factors, cytokines and cytokine receptors and signaling molecules essential to establish regulatory networks supporting Th17 or TR cells. This suggests that BMPR1α is a potential target to augment effector Th cell responses.

Effector CD4+ T cells activated by dendritic cells (DCs) expressing BMP inhibitors expressed lower levels of PD1. To block BMPs from acting on T cells, we will use DCs expressing noggin or gremlin that bind BMPs and prevent them from binding cellular receptors. Using DCs modified for immunotherapy to deliver BMP inhibitors will ensure that inhibitors are secreted in close proximity to T cells being activated; moreover, DCs are likely to persist longer than purified proteins. Both noggin and gremlin proteins are not produced by naive and activated T cells and are not produced by RM-1 prostate cancer cell lines. In a complementary approach, we will use a small molecule inhibitor of BMPR1α – LDN193189 (much more specific than dorsomorphin). The proposed experiments will provide a proof of principle that BMPR1α can be targeted to modulate immune response and we will determine the sensitivity of effector and TRsubsets to treatment.

Session Title

Poster Session

Location

Learning Commons @ Perry Library, Northwest Atrium

Start Date

2-2-2019 8:00 AM

End Date

2-2-2019 12:30 PM

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Feb 2nd, 8:00 AM Feb 2nd, 12:30 PM

Modulation of BMPR1α Function for Cancer Immunotherapy

Learning Commons @ Perry Library, Northwest Atrium

Despite increased understanding of how the transforming growth factor-β (TGF-β) regulates T cell functions, the immunomodulatory roles of other members of the TGF-β cytokine family, especially bone morphogenetic proteins, remain largely unknown. We have found that Bone Morphogenic Protein Receptor 1α (BMPR1α, Alk-3) expressed by activated effector and regulatory CD4+ T cells, modulates functions of both of these cell types by promoting generation of adaptive TR and inhibiting generation of Th17 cells from naive CD4+ T cells. Mice where BMPR1α is deleted in T cells (BMPR1αT- mice) had a decreased proportion of thymic derived TR cells. Activation of BMPR1α deficient (BMPR1α-) CD4+ T cells leads to generation of Th1/Th17-like effector cells expressing high levels of inflammatory cytokines, including IFN-γ, IL-17 and TNF family proteins. Immunization of BMPR1αT- mice induced vigorous inflammatory response and mice were able to better control B16 melanoma tumors. Tumor infiltrate had very few TR cells and higher proportion of CD8+ T cells compared to tumors in wild type mice. These data demonstrate that TGF-β mediated immunosuppression in the course of tumor growth can be bypassed by inhibition of BMPR1α signaling.

Transcriptome analysis of wild type and BMPR1α- CD4+ Th cells revealed differential expression of transcription factors, cytokines and cytokine receptors and signaling molecules essential to establish regulatory networks supporting Th17 or TR cells. This suggests that BMPR1α is a potential target to augment effector Th cell responses.

Effector CD4+ T cells activated by dendritic cells (DCs) expressing BMP inhibitors expressed lower levels of PD1. To block BMPs from acting on T cells, we will use DCs expressing noggin or gremlin that bind BMPs and prevent them from binding cellular receptors. Using DCs modified for immunotherapy to deliver BMP inhibitors will ensure that inhibitors are secreted in close proximity to T cells being activated; moreover, DCs are likely to persist longer than purified proteins. Both noggin and gremlin proteins are not produced by naive and activated T cells and are not produced by RM-1 prostate cancer cell lines. In a complementary approach, we will use a small molecule inhibitor of BMPR1α – LDN193189 (much more specific than dorsomorphin). The proposed experiments will provide a proof of principle that BMPR1α can be targeted to modulate immune response and we will determine the sensitivity of effector and TRsubsets to treatment.