AS741 - Impact of genetic susceptibility on colorectal tumor immune profile

Investigator Names and Contact Information

Introduction/Intent

During my postdoctoral training at Fred Hutchinson Cancer Center, I am receiving training and mentorship from Drs. Riki (Ulrike) Peters and Amanda Phipps in the integrative tumor epidemiology of colorectal cancer (CRC). This newly evolving discipline involves the integration of multiple domains of exposure and outcome measurements to understand the complex relationships between exposures that impact heterogeneous diseases, such as CRC. Utilizing the resources of the Genetics and Epidemiology of Colorectal Cancer Consortium, I aim to understand the relationships between germline genetics and tumor immune profile– and the impact of these relationships on CRC survival. In the mentored K99 phase of this early K99/R00 grant, I will leverage ongoing studies and focus on assessing these associations with T cell subsets (i.e., the predominant immune cells in CRC). In the independent R00 phase, I will then expand this work to more holistically examine associations with immune cell types beyond T-cells using PhenoCycler spatial profiling technology. Findings from this work will help uncover survival factors for more precisely measured CRC tumor phenotypes and, in doing so, may improve CRC prevention and treatment. I will also learn novel approaches in molecular epidemiology, such as methods to conduct spatial profiling to improve understanding of CRC etiology and severity. The K99/R00 will further advance my progress towards an independent research career as an academic professor of cancer molecular epidemiology studying novel methods to improve understanding of CRC.

Specific Aims

Colorectal cancer (CRC) is a critical public health issue as the third most commonly diagnosed cancer and second leading cause of cancer death globally.1 Cancer immunotherapy has become an important treatment option for CRC in recent years, holding promise in harnessing the host’s immune system to fight cancer. The presence of tumor infiltrating lymphocytes (TILs) in CRC, as an indicator of immune response to cancer, has been associated with immunotherapy response2 and CRC prognosis.3,4 Thus, identifying factors associated with tumor immune profiles holds relevance for better targeting cancer treatment and predicting outcomes.

Emerging evidence suggests germline genetics may also play a role in tumor immune profile.5,6 Identifying genetic predictors of tumor immune response may improve our understanding of the basis for heterogeneity in CRC clinicopathology and outcomes and improve our ability to identify which patients may be best suited for certain cancer therapies and point to novel target genes. For example, germline genetic variation in human leukocyte antigen (HLA) variants have previously been associated with immune-related phenotypes,7 and HLA allele HLA-A*03 specifically has been associated with response to immune checkpoint inhibitors.8 Polygenic risk scores (PRS) related to immune response have also been implicated in immune profile and survival, where a PRS associated with high risk of psoriasis has been associated with longer overall survival with a PD-L1 inhibitor compared to chemotherapy.9 However, further research is needed to identify which components of immune profile are linked to both germline genetic variation and survival. While T-cells are well-studied, increasing evidence shows that other immune cell types, such as natural killer cells, also impact the tumoral immune response and have high heritability, supporting a role for multiple immune cell types and germline genetics in tumor microenvironment composition.6

The objective of this project is to improve understanding about relationships between germline genetic variation and components of tumor immune profile, and associated implications for CRC-specific survival. In the K99 phase of this early K99/R00 grant, I will leverage ongoing studies and focus on assessing these associations with T cell subsets (i.e., the predominant immune cells in CRC). In the R00 phase, I will then expand this work to more holistically examine associations with immune cell types beyond T-cells (e.g., natural killer cells). Utilizing the resources of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), my specific aims are:

Specific Aim 1. (K99) Test whether germline genetic variation is associated with tumor immune profile in CRC, as measured by density of T-cell subsets (N=2500), using:

a) An agnostic genome-wide association study (GWAS) approach.
b) Polygenic risk scores (PRS) of phenotypes related to immune response such as inflammation or auto-immune disease to investigate shared genetic etiology.

Specific Aim 2. (R00) Using PhenoCycler spatial profiling to expand investigation to additional immune profile subsets beyond T-cells (e.g., macrophages, natural killer cells, dendritic cells, etc, N=1000):

a) Determine which immune profile subsets (beyond T-cells), as well as which cellular neighborhoods derived from immune spatial profiling, are associated with CRC-specific survival.
b) Test whether germline genetic variation (agnostic GWAS, inflammation or auto-immune PRS) is associated with aspects of tumor immune profile (beyond T-cells).
c) Investigate whether the association between germline genetic variation (GWAS and/or PRS) and CRC-specific survival is mediated by tumor immune profile.

The successful completion of these aims will expand our understanding of the relationships between germline genetics and tumor immune profile in the context of CRC. The long-term goal of this work is to improve our understanding of which patients may respond to what immune-related treatments more effectively by building knowledge around the genetic influences on tumor immune profiles.