Graduation Date

Spring 5-7-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Immunology, Pathology & Infectious Disease

First Advisor

James E. Talmadge

Abstract

In 2022, an estimated 62,210 people will be diagnosed with pancreatic ductal adenocarcinoma (PDAC) and approximately 49,830 will die from the disease. Current treatment strategies for gastrointestinal (GI) cancer patients, such as PDAC, have shown limited benefit, suggesting the need to develop novel, multimodality therapeutic approaches. Adoptive cellular therapy (ACT) using autologous tumor infiltrating lymphocytes (TILs) has shown efficacy in patients with melanoma; however, this approach is costly and requires extensive cell culture for sufficient numbers of T-cells for infusion. GI cancer patients with borderline resectable disease, whose primary tumor is adjacent to the splenic vasculature, can sometimes undergo a splenectomy as standard of care as the pancreas and spleen share the same blood supply, making the spleen a potential site for metastasis. The spleen provides an unutilized source of lymphocytes with potential utility for ACT, but few studies have examined the immune profile, or the effect of neoadjuvant chemotherapy (NCT) on the immune profile, in the spleen and peripheral blood (PB) in cancer patients. To address these questions, we undertook flow cytometric and clustering analyses on leukocyte populations, and the impact of NCT on patient immunity, in the spleens and PB of cancer patients, and compared these to both normal donors and patients with benign GI tumors. These studies provided several novel observations: first that the spleen is a rich source of CD8+PD-1+ T-cells with low expression of checkpoint proteins and potential utility for ACT. Secondly, we observed significant differences in the frequency and phenotype of myeloid-derived suppressor cells (MDSCs) in the PB and spleen of GI cancer patients as compared to the PB of normal donors, some of which were specific to the tissue type or source analyzed. Third, we report that, ~6 weeks post NCT, the immune profile of NCT treated cancer patients has recovered; this suggests that post-surgical resection patients may be more responsive to immune intervention. In addition, we report preliminary peripheral studies during which we assessed the function of CD8+PD-1+ T-cells from the spleens of GI cancer patients.

Winslow_Terese thesis copyright permission formSIGNED.pdf (340 kB)
Copyright Permission_ Winslow

Rightslink® by Copyright Clearance Center_Elsevier_second mx.pdf (120 kB)
Copyright Permission_Mx II

Rightslink® by Copyright Clearance Center MX III.pdf (126 kB)
Copyright Permission_MX III

Rightslink® by Copyright Clearance Center_Elsevier_First mx.pdf (123 kB)
Copyright Permission_MX I

RightsLink Printable License_book chapter with SK.pdf (158 kB)
Copyright Permission_Review I

RightsLink Printable License_book chapter with KP.pdf (197 kB)
CopryRight Permission_ Review II

Rights link T-mem image.pdf (231 kB)
Copyright Permission_Tmem

JAMA.pdf (119 kB)

Available for download on Saturday, September 10, 2022

Included in

Therapeutics Commons

Share

COinS