# Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2021 · $433,439

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunotherapies hold immense promise to provide cures for many cancers and metastatic disease, but only
benefit a fraction of patients. Tumors can still engage multiple mechanisms to avoid and escape anti-tumor
immune responses, including suppression, inactivation, and exclusion of potential cytotoxic T cells, processes
which collaborate with cells in the tumor microenvironment (TME). A better understanding of these barriers has
led to a multitude of new immunomodulatory targets to be developed, some to be used in combination with
e.g., checkpoint blockade or CAR T cells. On the other hand, dominant barriers to immunotherapy can be
different among patients with the same cancer type, and thus there is a need for personalized approaches to
immunotherapy, so that the appropriate targets are used. Here we develop a novel organotypic culture devices
to maintain ex vivo cultures of primary tumors and an immune component (tumor-draining lymph nodes or
circulating leukocytes), on a platform that enables precise control over spatial, molecular, cellular, and
mechanical characteristics and that is relatively high-throughput to allow screening or large numbers of
experimental variables. In preliminary data, we show that these devices mirror key features of in vivo
responses to immunotherapy, such as improved tumor cell killing and increased markers of immunotoxicity
(possible adverse events) in response to cytokine immunotherapy. We propose that these devices can be used
both to screen for ideal immunotherapy combinations as well as to probe the basic mechanisms underlying the
deficiencies in the anti-tumor immune response for tumors exhibiting varying levels of immune infiltration,
neoantigen load, and baseline lymphatic densities. In this way, we can begin to build a stratification map that
aligns key morphological features of individual tumors to treatment regimes that are most likely to lead to
efficacy and tumor regression. Using a combination of both murine mouse models and primary patient-derived
biospecimens, we will take advantage of the level of control afforded by our novel organotypic devices to
mechanistically interrogate individual immune cell subsets and signaling axes, towards understanding their
roles in influencing the course and outcomes of anti-tumor immune responses.

## Key facts

- **NIH application ID:** 10299447
- **Project number:** 1R01CA253248-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Melody Ann Swartz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,439
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299447

## Citation

> US National Institutes of Health, RePORTER application 10299447, Probing cellular, molecular and biomechanical barriers to immunotherapy in the tumor microenvironment with organotypic in vitro models of the tumor-lympho-immune interface (1R01CA253248-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10299447. Licensed CC0.

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