# Systems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule Drugs

> **NIH NIH U54** · HARVARD MEDICAL SCHOOL · 2021 · $253,500

## Abstract

SUMMARY ABSTRACT
 Single cell RNA profiling and DNA sequencing has revolutionized our understanding of the tumor
microenvironment (TME) but such data lacks the spatial context and morphological information found in
images. Histology makes extensive use of morphology, and in a clinical setting provides the primary means of
diagnosing disease and managing treatment. However, relatively little molecular insight can be obtained from
classical Hematoxylin and Eosin (H&E) or immunohistochemistry. These considerations have led to the recent
development of multiple methods for performing highly multiplexed tissue imaging. It allows the properties of
single cells to be determined in a preserved 3D environment in humans and mouse models. In a research
setting, multiplexed imaging provides new insight into molecular mechanisms of tumor initiation, progression,
immune editing, and escape. In a clinical setting, high-plex imaging promises to augment the traditional
histopathological diagnosis of disease with molecular information needed to guide use of targeted and
immuno-therapies. Multiple high-plex tissue images yield subcellular resolution data on 20-100 proteins or
other biomolecules on resolvable structures having spatial scales from 100 nm to over 1 cm in specimens as
large as 5 cm2. These images contain 106 to 107 cells, encoded in up to 1 TB of data.
The primary barrier to wider use of high-plex imaging centers on the computational challenges associated with
processing, managing, and disseminating images of this size. Many algorithms and methods have been
developed to process images of cells grown in culture and these provide a foundation for analysis of tissue
images. However, high-plex tissue imaging poses many additional challenges arising from the diversity and
crowding of cells and as well as the size of the data. We have constructed a cloud-deployed pipeline
(MCMICRO) that uses Docker-containers and a NextFlow pipeline to process large-scale tissue images and
generate single-cell data in a standardized format. We propose to reengineering the components of this proof-
of-concept implementation to make it performative and broadly useful. Aim 1 will improve the performance of
individual modules through code profiling and optimization. Aim 2 will complete the general user and
programmer documentation of MCICRO and its modules to enable continued contributions from the open-
source community and to increase interoperability and perform testing. Aim 3 will add modules to MCMICRO
based on existing proof-of concept code available in the public domain. Aim 4 will enable output of pipeline
intermediate and final results - including image data itself - from the cloud without requiring download. These
supplementary aims are directly relevant the approved aims of the parent award. Completing these aims will
involve partial reengineering of existing software modules and evaluation of pipeline performance using real-
world test data that we will release as pa...

## Key facts

- **NIH application ID:** 10405812
- **Project number:** 3U54CA225088-04S1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** PETER Karl SORGER
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $253,500
- **Award type:** 3
- **Project period:** 2021-06-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405812

## Citation

> US National Institutes of Health, RePORTER application 10405812, Systems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule Drugs (3U54CA225088-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405812. Licensed CC0.

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