Interrogating Immunomodulation for Anti-Metastatic Therapy

PROJECT SUMMARY This proposal outlines a five-year career development program for Chris McGinnis, Ph.D. to prepare him for an independent research career in cancer immunology to study tumor-immune interactions during metastasis. The candidate will conduct his postdoctoral training at Stanford University, which provides an outstanding environment to complete the proposed research. Dr. McGinnis’ mentors and advisors, including Drs. Satpathy, Kuo, Engleman, Reticker-Flynn, and Engreitz, have diverse technical expertise relevant to all aspects of the proposal and track records of guiding trainees to independence. Further, the candidate will utilize world-class resources available through the Stanford Office of Postdoctoral Affairs to acquire career development skills. Additionally, the research infrastructure within his mentors’ labs will enable him to efficiently perform the scientific aims, receive training in areas encompassed by this proposal, and transition to independence. The goal of this work is to demonstrate the utility of Dr. McGinnis’ innovative research program – namely, coupling longitudinal single-cell RNA-sequencing (scRNA-seq) and chemical compound high-throughput screening (HTS) to improve our understanding of pro-metastatic immune remodeling mechanisms and discover the first-generation of anti-metastatic immunotherapies. The role of tumor-mediated immune remodeling during metastasis is well-established, positioning immunotherapeutic approaches as an attractive paradigm for limiting metastasis. However, our understanding of these mechanisms remains incomplete, and existing HTS platforms are ill-suited to identify drugs which effectively operate in the metastatic nice. In Aim 1 (K99), Dr. McGinnis will demonstrate how longitudinal scRNA-seq analysis of the metastatic niche can uncover novel mechanisms of pro-metastatic immune remodeling by formally assessing whether IGF1 signaling between lung neutrophils and tissue-resident macrophages regulates early organization of the pre- metastatic niche. In Aim 2 (K99), the candidate will benchmark and optimize an ex vivo lung tissue culture HTS platform which will be used to analyze immune perturbation responses in the metastatic niche using scRNA-seq. After transitioning to a faculty position for Aim 3 (R00), Dr. McGinnis will focus his efforts on performing the first anti-metastatic immunotherapy chemical compound screen to identify drugs that effectively inhibit myeloid TLR- NFκB inflammation in the lung metastatic niche. Together, the pursuit of this research will provide critical insights into how tumors use the immune system to spread and identify anti-metastatic immunotherapy candidates. All protocols, data, analytical frameworks, and software tools that are produced during the duration of this research will be freely distributed. Moreover, the proposed project will serve as an effective training program for Dr. McGinnis to launch his independent career as a tenure-track investigator.