Il-1Α Blockade Reduces Immune Suppression In The Early Tumor Micro-Environment

<p>IL-1α Blockade Reduces Immune Suppression in the Early Tumor Micro-Environment</p> <p>Brenda Melendez, B.S.</p> <p>Advisory Professor: Gregory Lizee, PhD.</p> <p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Authors dc:creator

• Melendez, Brenda
• <p>https://orcid.org/0000-0001-8789-6791</p>

Contributors dc:contributor

• Gregory LIzee
• Michael Curran
• Chantale Bernatchez

• IL-1
• tumor micro-environment
• melanoma
• immunosuppression
• cytof
• immune cells
• Immunopathology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/919

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1967