# T Cell Receptor Forces: From Molecular Mapping to Cancer Therapeutic Triggering

> **NIH NIH K00** · HARVARD UNIVERSITY · 2021 · $89,584

## Abstract

T cells migrate through tissues, scanning cell surfaces and selectively destroying infected or
malignant cells. The T cell interacts with other cells through the T cell receptor (TCR),
recognizing antigen peptide fragment bound to the major histocompatibility complex (pMHC), on
target cells. The TCR-pMHC bond is extremely specific, recognizing a single target pMHC
among a myriad of other antigens. Despite the extreme importance of the TCR-pMHC bond to
cancer prevention and immune surveillance, the origin of TCR specificity remains unclear.
There is indirect evidence that TCR recognition of antigen utilizes uses mechanical force,
specifically piconewton forces parallel the T cell membrane, to differentiate foreign antigen from
self-antigen. Additionally, only one or two TCR-pMHC molecular bonds may be sufficient to
trigger T cell activation, but tools to map pN mechanical events and to measure the orientation
of these forces of do not exist, hindering progress in understanding T cell mechanobiology.
 My PhD research focuses on developing tools for molecular mechanobiology. I have
invented a technique, Molecular Force Microscopy, capable of mapping the 3D orientation of
piconewton molecular forces. I have also invented tension-PAINT, a super-resolved imaging
technique capable of mapping single molecule cellular forces with ~10 nm spatial resolution. My
F99 research has two focuses. First, I will apply Molecular Force Microscopy in conjunction with
biochemical markers of T cell activation (e.g. Zap70-EGFP and calcium signaling) to test the
hypothesis that TCR prefers forces parallel to the cell membrane to activate in response to
antigen. Second, I will apply tension-PAINT to T cell forces to test the hypothesis that molecular
forces recruit co-receptors in a force-dependent manner during T cell activation. This research
will provide vital mechanistic details about force-mediated T cell activation.
 For my postdoctoral (K00) work, I will transition to developing immunotherapuetics.
Immunotherapies, including engineered immune cells and PD-L1 blocking antibodies, have
been deployed as anti-tumor therapies. However, immunotherapy is ineffective in many
cancers. I hypothesize that TCR forces at the T cell-tumor junction can be leveraged to create
new, force-activated immunotherapeutics. I will create a DNA-based container which I have
termed the DNA origami antigen (DOA). The DOA will bind to tumor cells via cancer-specific
antibodies. T cell forces will open the container, revealing a highly immunogenic payload that
will stimulate cytotoxic T cell killing of cancer therapeutic. This research will result in a novel
class of molecular force activated immunotherapeutics to combat cancer.

## Key facts

- **NIH application ID:** 10247093
- **Project number:** 5K00CA234959-04
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Joshua Mark Brockman
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $89,584
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247093

## Citation

> US National Institutes of Health, RePORTER application 10247093, T Cell Receptor Forces: From Molecular Mapping to Cancer Therapeutic Triggering (5K00CA234959-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247093. Licensed CC0.

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