Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with an average survival of six months following diagnosis. Novel therapies to prolong survival include immune-based approaches. Importantly, key effectors of anti-tumor immunity against PDAC are tumor-associated macrophages (TAMs), which abound in the tumor microenvironment of PDAC. The capacity of TAMs to phagocytose and kill tumor cells is governed by pro- and anti-phagocytic signals found on these cells. Pro-phagocytic signals include clinically-approved antibodies that bind to PDAC cells expressing epithelial growth factor receptor (EGFR). Upon binding tumor cells, anti-EGFR antibodies abate pro-oncogenic signaling and elicit anti-tumor immunity. However, anti-EGFR antibodies have shown limited clinical benefit for PDAC patients. The priority of this proposal will be to promote antibody- dependent cellular phagocytosis (ADCP) of PDAC cells by TAMs during treatment with anti-EGFR antibodies. An anti-phagocytic molecule that I have found to be present on PDAC is CD47. CD47 functions in many cancers to suppress phagocytosis of tumor cells by binding to SIRPa-receptor on TAMs.
Aim 1 will examine the consequence of CD47-inhibition on the phagocytosis of PDAC cells by TAMs. The anti-phagocytic role of CD47 is counterbalanced by pro-phagocytic signals such as tumor-bound anti-EGFR antibodies. These antibodies trigger phagocytosis by engaging Fc-receptors (FcRs) on TAMs. Notably, FcR subsets expressed by TAMs may stimulate or inhibit their activity, and the relative abundance of FcR subsets varies between pro- and anti-inflammatory macrophage phenotypes.
Aim 2 will study EGFR on tumor cells as well as FcR- expression by TAMs in coordinating ADCP. By understanding the role of pro-and anti-phagocytic signals in governing ADCP, this proposal aims to deploy macrophage-based immunotherapies to potentiate tumor- targeting antibodies against PDAC.

Public Health Relevance

Pancreatic cancer is the fourth-leading cause of cancer deaths in the US, making new therapeutic strategies a crucial imperative. Immune-based treatments represent a promising strategy for achieving durable anti-tumor responses. To this end, my proposal will investigate pro- and anti-phagocytic signals on pancreatic cancer cells as targets for potentiating novel macrophage-based immunotherapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30CA196124-01
Application #
8908729
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2015-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Liu, Mingen; Kalbasi, Anusha; Beatty, Gregory L (2017) Functio Laesa: Cancer Inflammation and Therapeutic Resistance. J Oncol Pract 13:173-180
Kalbasi, Anusha; Komar, Chad; Tooker, Graham M et al. (2017) Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:137-148