Evading immune responses is a hallmark of cancer. The `tumor-immunity cycle' begins with the processing of tumor-associated proteins by dendritic cells (DC), which initiate a T-cell response in draining lymph nodes, followed by the trafficking of these anti-tumor T cells into the tumor to mediate tumor lysis. Tumors can block one or more steps of this cycle to evade immune responses. The therapeutic potential of targeting such immune-evasion pathways is highlighted by the clinical success of immune checkpoint inhibitors that alleviates T cell suppression in cancer. However, tumor-reactive T cells are not generated in most solid tumors, which limit the utility of immune checkpoint inhibitors. A major reason for this failure to generate anti-tumor T cells is the paucity and dysfunction of DCs in the tumor microenvironment (TME). While DCs are rare inside tumors, a closely related cell type, macrophages, are abundant. In contrast to DCs, tumor-associated macrophages (TAMs) are immunosuppressive and promote tumor progression. Both DCs and TAMs can originate from monocytes but there is a major knowledge gap in our understanding of why monocytes preferentially differentiate into immunosuppressive TAMs but not immunostimulatory DCs in solid tumors. Our long-term interest is to understand the development and differentiation of macrophages and DCs in the TME with the overarching goal of targeting these cells for cancer immunotherapy. I previously developed powerful genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as mouse models to study antigen-presenting cells. Using these tools in my laboratory, I recently discovered that tumor cell-derived retinoic acid blocks DC but promotes TAM differentiation from monocytes. Furthermore, I have found that the cytokine IL13 promotes RA production in tumor cells. Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the generation of immunostimulatory DCs from TME monocytes. I posit that this is a major pathway of immune evasion in solid tumors. Our two specific aims will delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1) and uncover how IL13 controls RA production in TME (Aim 2). We will also examine the value of targeting this pathway for tumor immunotherapy. This work will have significant impact on our understanding of immunomodulation in solid tumors and establish a new approach in solid tumor immunotherapy based on targeting RA signaling in APCs. Our work is innovative because it will open new avenues of research into the role of retinoid signaling in APC differentiation and tumor immunity.

Public Health Relevance

Solid tumors present a significant public health issue despite intense research and advances in patient care. Recent research demonstrates that tumors avoid detection by the immune system to progress but the underlying mechanisms are poorly understood. Our work will delineate a novel pathway of immune evasion in solid tumors and provide proof of concept of targeting this pathway for tumor immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
1R37CA234027-01
Application #
9641315
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Howcroft, Thomas K
Project Start
2018-12-03
Project End
2023-11-30
Budget Start
2018-12-03
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104