Student Theses and Dissertations

Date of Award

2016

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Krueger Laboratory

Abstract

Melanoma is a life-threatening malignant disease, of which the standard of care treatment is rapidly becoming immunologically driven, due to favorable recent clinical trials using immune checkpoint inhibitors. Diphencyprone (DPCP), a topically applied contact sensitizer, has been used with an 84% success rate to treat cutaneous melanoma metastases, but the immune mechanisms underlying its efficacy are largely unknown. This thesis characterizes skin immune reactions induced by DPCP, both in healthy volunteers and patients with metastatic melanoma. In healthy volunteers, DPCP led to upgregulation of many immune molecules that may be anti-neoplastic effectors, including IFNγ, IL-24, and IL-9. We also examined the potential roles of miRNAs in skin reactions to DPCP, as they may be involved in its therapeutic applications, but are largely unstudied in skin biology and immunology. Furthermore, we used comprehensive T cell receptor sequencing to show that the immune reactions induced by DPCP are polyclonal, and therefore suggests that the induced inflammation is not due to a single antigen. Also, different individuals expanded different T cell clones in response to the same application of DPCP, which could mean that DPCP is conjugating with unique proteins in each person. This may have relevance to the action of DPCP in melanoma patients, as each treated patient may expand a unique repertoire of T cells specific to antigens found only in that patient. In sum, this work with healthy volunteers formed a basis for investigating specific immune elements that may be induced in melanoma lesions that are treated with DPCP, as well as the baseline immune competence of cancer patients. It also led to insights regarding the regulation of immune responses, and provides a useful comparison point to inflammatory skin diseases such psoriasis. Our clinical trial with metastatic melanoma patients allowed us to more directly study the immunologic mechanisms underlying the efficacy of DPCP to treat skin metastases. Six patients enrolled in the study, and although each had a unique treatment course, 5 demonstrated at least partial melanoma regression in response to DPCP treatment. In these patients, we observed a shift towards Th1 polarization with the repeated DPCP applications required for treatment efficacy. This shift is likely relevant to melanoma treatment, as Th1 cells have established roles in anti-melanoma responses. To further support this, one of our patients who had both a regressing and non-regressing metastasis in response to DPCP, had increased expression of Th1-defining molecules in the former. A different patient, who received DPCP with checkpoint inhibitor therapy, provided proof of concept that these two immunotherapeutics can act synergistically. Overall, this work provides varied insights into cutaneous immune responses, and how they can be successfully employed in the context of skin cancer therapy.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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