Date on Master's Thesis/Doctoral Dissertation

12-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Degree Program

Microbiology and Immunology, PhD

Committee Chair

Bodduluri, Haribabu

Committee Co-Chair (if applicable)

Shirwan, Haval

Committee Member

Shirwan, Haval

Committee Member

Kosiewicz, Michele

Committee Member

Yan, Jun

Committee Member

Galandiuk, Susan

Author's Keywords

anti-tumor immunity; melanoma; CTL infiltration to tumors; PD-1 blockade; LTB4; CXCL9 and CXCL10

Abstract

Presence of increased numbers of CD8+ T cells in the tumors correspond to better overall survival in the patients. Variety of immuno-therapies have shown considerable efficacy in the clinic, however, a multitude of patients remain unresponsive. Most of these immunotherapies rely on effector T cell responses in the tumor. A major obstacle in the success of these immunotherapies is poor recruitment of CD8+ T cells into tumors despite intact effector responses in the periphery. Therefore understanding the mechanisms that regulate CTL infiltration into tumors becomes essential. Previous studies in our laboratory suggested an important role for BLT1 in immune surveillance against tumors by regulating CTL migration in a syngeneic cervical cancer tumor model. In this thesis, we investigated the roles of leukotriene B4 (LTB4) receptor - BLT1; and CXCR3, the receptor for CXCL9, CXCL10 and CXCL11 in anti-tumor immunity using a syngeneic B16 melanoma tumor model. BLT1-/- mice and CXCR3-/- mice on a C57BL/6 background were used to examine the function of these receptors in tumor progression. Significant acceleration in tumor growth and reduced survival was observed in both BLT1-/- and CXCR3-/- mice as compared to the WT mice. Analysis of tumor infiltrating leukocytes revealed significant reduction of CD8+ T cells in the tumors of BLT1-/- and CXCR3-/- mice as compared to WT tumors; their frequencies being similar in the periphery (spleen and TdLN). Significant reduction of Granzyme-B and IFNγ transcripts were observed in tumors of knockout mice compared to WT mice. Adoptive transfer of tumor experienced WT but not BLT1-/- or CXCR3-/- CD8+ T cells reduced tumor growth significantly in Rag2-/- mice, which correlated with reduced infiltration of knockout CD8+ T cells into tumors. Co-transfer of WT CD8+ T cells with either of the knockout CD8+ T cells in tumor bearing Rag2-/- mice showed that WT CD8+ T cells did not facilitate additional knockout CD8+ T cell infiltration to tumors. BLT1/CXCR3 double deficient mice displayed similar tumor kinetics as single knockout mice and showed lack of synergism. The requirement for BLT1 and CXCR3 in inducing checkpoint blockade mediated anti-tumor response was tested. While anti-PD-1 based vaccine significantly attenuated tumor growth in WT mice, the vaccine completely lost its efficacy in BLT1-/-, CXCR3-/- or BLT1-/-CXCR3-/- mice that correlated with failure of knockout CD8+ T cell infiltration into tumors. These results demonstrate a critical role for BLT1 and CXCR3 in CTL migration to tumors and thus can be targeted to enhance effective anti-tumor responses.

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