Tumor microenvironment (TME), particularly tumor-infiltrating inflammatory cells, is an essential component of tumorigenesis. Most of the solid tumors demonstrate a paradoxical ability to recruit immune cells and to upregulate inflammatory mediators which assist tumor progression. We first defined this process as ?Tumor elicited inflammation? (TEI) and suggested that in colorectal cancer (CRC), TEI is induced early during the tumorigenesis, particularly because of the oncogene-induced, tumor specific deterioration of barrier and microbial product translocation. Inhibition of inflammation by general anti-inflammatory drugs or by specific inactivation of inflammatory signaling nodes (cytokines, transcription factors) decreases tumor incidence and growth in animal models and reduces the risk of cancer development and related death in humans. Unresolved questions are how TEI is induced by tumors, what are the critical mediators of TEI maintenance and its pro- tumorigenic action and how TEI acts to promote cancer and what are the time requirements for TEI action? Here we will uncover TEI mechanisms in CRC. From our previous work and preliminary data it is known that IL-23 regulates the IL-17 pathway that is essential for CRC growth. However, the identity of CRC-specific microbial stimuli, as well as the identity of myeloid cells producing IL-23 and the identity of IL-23R expressing, IL-23-responsive cells is not known. Furthermore, while it is likely that TEI promotes CRC during later stages of tumor development, it is not known whether ?early? TEI induction during CRC inception is important for CRC outgrowth. Based on preliminary data we hypothesize that strongly adhesive bacteria stimulate IL-23 expression in tumor myeloid cells and IL-23 activates pro-tumorigenic IL-17 production from T cells and innate lymphoid cells (ILC) to promote CRC by acting within CRC TME, and that mechanisms operate even in early CRC. Proposed Specific Aims which are modified for the revised application are the following: (1) Define the tumor-specific microbial stimuli required to control TEI in CRC. (2) Define subsets of tumor myeloid cells required for IL-23 production and TEI induction in CRC; and 3) Examine microenvironmental mechanisms of IL-17 TEI mediated CRC and temporal requirements for TEI during CRC promotion. Overall, these studies represent a comprehensive approach integrating immunology, genetics and cancer biology to yield basic insights into the role of specific microbes in inducing TEI to promote CRC. We will methodically test various cell compartments within the TME responding to CRC-specific microbial signals, producing IL-23 and responding to IL-23; and how TEI drives CRC via its action on cells within the CRC TME. This will be a key to understand how inflammatory and cancer cells communicate within the Tumor Microenvironment and will identify targets for novel preventive/therapeutic breakthroughs. This work will establish a rationale for the specific elimination of risk-associated populations of microbes and neutralization of cytokine pathways within the CRC TME as a means of limiting CRC progression.

Public Health Relevance

Tumor-elicited inflammation (TEI) modulates TME in colorectal cancer (CRC) and other cancers, which are a great threat to public health. Our studies will methodically dissect mechanisms of TEI CRC from their inception to their action on cancer cells and cells of CRC microenvironment. Altogether, our findings should aid the creation of novel therapeutics and preventive measures as well as point out novel important TME-based biomarkers of CRC, all of which may also be applicable to other cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA218133-03
Application #
10245810
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Daschner, Phillip J
Project Start
2020-09-01
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048