Optimizing T and myeloid cell function in chronic viral infection and cancer.

9780438194410

Ann Arbor : ProQuest Dissertations & Theses, 2018

1 online resource (109 p.)

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Chronic viral infections and cancer are major causes of morbidity and mortality around the world. These pathological states persist in part because of inadequate functional responses by T and myeloid cells. Furthermore, cytotoxic T lymphocytes (CTL) autonomously downregulate their function by upregulating inhibitory receptors such as programmed cell death 1 (PD1) and prostaglandin E2 (PGE2) receptors EP2 and EP4. Myeloid cells upregulate ligands for these inhibitory receptors, including programmed cell death ligand 1 (PD-L1) and PGE2. In addition, cytokine production by CTLs and myeloid cells is crucial in modulating both these interactions and effecting control of viral and tumor proliferation. Elucidating mechanisms of CTL and myeloid cell (dys)function during persistent pathological states is a critical unresolved problem. We showed that the combined blockade of PGE2 and PD 1 signaling was therapeutic in terms of improved viral control and augmented numbers of functional virus-specific CTLs. Furthermore, we have found that combination therapy with agonistic CD40 antibody and inhibition of CSF1R signaling improved the therapeutic response of either agent alone in an autochthonous, poorly immunogenic mouse model of melanoma. Combined CD40 and CSF1Ri therapy induced a marked increase of inflammatory cytokine production by tumor associated macrophages (TAMS) required for tumor control. Overall, we find that interventions focused on optimizing T and myeloid cell function can be instrumental in two persistent pathological states relevant to human disease.

Books / Online / Dissertations & Theses

English

January 09, 2019

Thesis (Ph.D.)--Yale University, 2018.

Yale University.