Author ORCID Identifier

https://orcid.org/0000-0001-8789-6791

Date of Graduation

12-2018

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Gregory LIzee

Committee Member

Michael Curran

Committee Member

Chantale Bernatchez

Committee Member

Jagannadha Sastry

Committee Member

Kwong Wong

Abstract

IL-1α Blockade Reduces Immune Suppression in the Early Tumor Micro-Environment

Brenda Melendez, B.S.

Advisory Professor: Gregory Lizee, PhD.

Immunotherapy against melanoma has shown great promise in the clinic for treating advanced-stage patients. However, a major barrier against effective T cell mediated cytotoxicity is immunosuppression in the tumor micro-environment. It has been described that tumors secrete pro-inflammatory cytokines capable of modulating immune responses that favors the growth of tumor cells. Specifically, IL-1 plays a critical role in myeloid cell recruitment and activation, which can in turn inhibit T cell activity in vivo. Moreover, IL-1 is also known to up-regulate immune inhibitory molecules in the tumor micro-environment. To further investigate the effects of IL-1 in melanoma progression, IL-1α was blocked in a highly aggressive pre-clinical B16 melanoma tumor model in three different treatment settings: as a monotherapy, in combination with checkpoint blockade, and in combination with adoptive T cell therapy. In all three settings, IL-1α blockade resulted in tumor reduction and increase in murine survival. This was accompanied by a decrease in myeloid cell tumor infiltration. At early time points following IL-1 α blockade, these myeloid cells also demonstrated partial loss of their immunosuppressive abilities, as supported by a decrease in arginase production and inhibitory molecule expression. Moreover, monocytes demonstrated an increase in co-stimulatory molecules following IL-1 α blockade. In vitro, the myeloid cells’ ability to inhibit T cell cytotoxicity was significantly compromised. These results collectively provide evidence in support of IL-1 α contributing to melanoma immune suppression. Antibody-mediated blockade of IL-1 α improved antitumor responses, suggesting that this modality may improve outcomes of patients undergoing treatment with T-cell based immunotherapies.

Keywords

IL-1, tumor micro-environment, melanoma, immunosuppression, cytof, immune cells

Available for download on Saturday, December 14, 2019

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