# Imaging tumor and T cell responses to metabolic and immune modulation

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $90,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Purpose of the project. This application focuses on the use of imaging to better understand, reverse, and
monitor immune suppression and metabolism in murine models of aggressive/metastatic breast cancer. High
LDH-A and monocarboxylate transporters 1 and 4 (MCT-1 and MCT-4) have been linked to poor prognosis,
and greater metastatic potential. Based on clinical analyses of GEO and MSKCC’s cBio Portal: i) tumors
with increased expression of genes involved in lactate metabolism are more aggressive and have poor
survival, and ii) there is an inverse correlation between the expression of glycolysis genes and immune-related
genes. These data support our hypothesis: that high rates of tumor glycolysis leads to a lactic acid-rich tumor
microenvironment (TME) with the exclusion of T cells, resulting in more aggressive tumors with a propensity to
form metastases. We further hypothesize that reversal of the T cell exclusion with metabolic inhibitors will
render tumors that are resistant to immune modulation with checkpoint blockade (CTLA-4, PD-1) to be
responsive to the treatment, due to repopulation of T cells within the tumor microenvironment.
Here, we propose to use multimodal imaging to explore the mechanisms by which metabolic and immune
modulation therapy reverse the restriction and inactivation of cytotoxic T cells in clinically relevant murine
models of aggressive breast cancer. We plan to: 1) characterize in vivo changes in tumor lactate and T cell
infiltration during LDH-A and MCT-1/4 inhibition; 2) evaluate the responses to adjuvant and neo-adjuvant single
and combination therapy (metabolic inhibition and “checkpoint” blockade in vivo); 3) validate the imaging
results by assessing correlations between glycolytic biomarkers and T cell infiltration using ex vivo
immunofluorescence (IF), immunohistochemistry (IHC), and fluorescence-assisted cell sorting (FACS); and 4)
assess the potential for clinical translation. The translational goal is two-fold: 1) to induce regression in primary
and metastatic breast cancer, by increasing tumor penetration and effector function of cytotoxic T cells, and 2)
to monitor treatment response by non-invasive imaging.
Experimental Strategy. We have established several murine models of aggressive breast cancer in immune
competent host animals. In Aim 1, in vitro and in vivo studies will define how tumor-cell metabolism affects T
cell function, and identify a “therapeutic window” for optimizing the magnitude and timing of T cell repopulation
of aggressive murine breast tumors following LDH and MCT pharmacologic inhibition. In Aim 2, metabolic and
immune-PET imaging will monitor how changes in the TME (induced by anti-LDH and anti-MCT treatment)
affect T cell infiltration and function. Based on Aim 1 and 2 studies, an “optimized” lactate inhibition treatment
strategy (established in Aims 1 and 2) will be combined with immune checkpoint blockade (anti-PD1 and anti-
CTLA4) and assessed in Aim 3. Ima...

## Key facts

- **NIH application ID:** 10729012
- **Project number:** 7R01CA215136-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Taha Merghoub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $90,974
- **Award type:** 7
- **Project period:** 2017-06-20 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10729012

## Citation

> US National Institutes of Health, RePORTER application 10729012, Imaging tumor and T cell responses to metabolic and immune modulation (7R01CA215136-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10729012. Licensed CC0.

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