# The ontogeny and function of CD8 T cells in lung cancer

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $217,653

## Abstract

PROJECT SUMMARY/ABSTRACT
Targeting the immune system to destroy cancer cells using immunotherapy has rapidly emerged as a promising
avenue for treating cancer, and has resulted in robust clinical responses in a subset of patients. While the initial
success stories have provided proof of concept that the immune system can be harnessed to treat cancer, the
majority of patients do not achieve long lasting or even initial benefit, highlighting the need to better understand
the barriers to successfully using the immune system to eliminate cancer cells. The focus of this proposal is non-
small cell lung cancer (NSCLC), which has only shown 20-40% of patients having an objective response to
immune based therapies to date. A major obstacle to improving current immunotherapies in lung cancer is a lack
of understanding of the overarching T cell response during tumorigenesis. Indeed, few studies have been able
to longitudinally dissect the CD8 T cell response in a physiological time frame in the native lung
microenvironment. Previous work has identified a population of less dysfunctional T cells in the tumor that
express the transcription factor T cell factor 1 (TCF-1), and it is this population that is thought to mediate
productive anti-tumor responses. However, how to generate these cells when they are lacking, the
developmental trajectories of these cells during tumorigenesis, and how to best target these cells for therapeutic
purposes remain unclear. The goal of this project is to address these critical questions surrounding the TCF-1+
subset of anti-tumor CD8 T cells using an autochthonous mouse model of lung adenocarcinoma that
recapitulates both the time scale and anatomical progression of human NSCLC. Utilizing cutting edge
methodologies and techniques, including single cell RNA sequencing, parabiosis and proximity labeling, we will
define the ontogeny, differentiation, function, and determinants that dictate the fate of responding anti-tumor
TCF-1+ CD8 T cells. In Aim 1, we will build on our preliminary data demonstrating heterogeneity within the TCF-
1+ CD8 T cell compartment by elucidating functionality and transcriptional status of anti-tumor CD8 T cell
populations. We will compare the transcriptomic data we generate in Aim 1 to existing human single cell RNA
sequencing to determine the relevance of the CD8 T cell states we identify in our model. In Aim 2 we will
determine the role of tumor-T cell interactions in T cell phenotype and fate using a proximity labeling system to
identify CD8 T cells that have recently interacted with tumor cells. In Aim 3, we will define the relationship of
lymph node and lung TCF-1+ CD8 T cells, and will attempt to therapeutically harness anti-tumor CD8 T cells
within the dLN to seed more TCF-1+ CD8 T cells into the tumor. Taken together, our aims are positioned to
redefine our understanding of the anti-tumor CD8 T cell response and potentially identify new therapeutic
avenues to treat cancer.

## Key facts

- **NIH application ID:** 10105475
- **Project number:** 1K08CA256044-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jason M. Schenkel
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $217,653
- **Award type:** 1
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105475

## Citation

> US National Institutes of Health, RePORTER application 10105475, The ontogeny and function of CD8 T cells in lung cancer (1K08CA256044-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10105475. Licensed CC0.

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