Effect of tumor cell glutamine metabolism on anti-tumor immunity in TNBC

PROJECT SUMMARY/ ABSTRACT
Breast cancer is the most common malignancy among western women. Although adjuvant and
molecularly targeted therapies significantly improve patient survival in some molecular subtypes
of breast cancer, the prognosis of triple-negative/basal-like breast cancer (TNBC) remains grim,
due to lack of identification of oncogenic drivers. In searching of cancer vulnerability, it was
discovered that TNBC is especially dependent on glutamine metabolism, likely due to up-
regulation of the glutamine transporter, ASCT2/SLC1A5, and glutaminase, GLS, representing
the rate-limiting steps in glutamine consumption. Despite the interest in targeting glutaminolysis
in TNBC, it is unclear how global inhibition of glutamine metabolism will affect immune cells in
the tumor microenvironment, particularly given that rapidly proliferating tumor infiltrating
lymphocytes (TILs) require glutaminolysis to supply macromolecules for cell growth.
Specifically, the competition between tumor cells and TILs for glutamine has not been
investigated thus far, but is likely to be important for anti-tumor immunity.
We have generated preliminary data providing evidence that knockout of GLS specifically in
tumor cells increases glutamine concentration in the tumor interstitial fluid and enhances
cytotoxic CD8 T lymphocyte activities. The above effects are abrogated in immune-deficient
mice, suggesting that adaptive immunity plays a critical role. In addition, pharmacologic
inhibition of the glutamine transporter, ASCT2, selectively targeting tumor cells while enhancing
TIL function. Based on these findings, we hypothesize that (1) tumor cells outcompete TILs for
glutamine to sustain their proliferative programs while simultaneously suppressing antitumor
immune response, and (2) selectively targeting glutamine metabolism in tumor cells enhances
antitumor immunity. To test these hypotheses, we will first test glutamine competition between
tumor cells and TILs and how this competition affects tumor growth, metastasis, and anti-tumor
immune responses (Aim 1). We will also define how metabolic changes in GLS loss specifically
in tumor cells impact T cell recruitment and activation in situ by MALDI-imaging mass
spectrometry (Aim 2). Finally, we will evaluate in vivo pharmacological targeting of glutamine
transporter and glutaminase for treating TNBC (Aim 3). The success of the project will elucidate
a long-standing issue whether there is a metabolic competition for glutamine between tumor
cells and infiltrating lymphocytes, and leverage the knowledge for developing new therapeutic
strategies for treatment of glutamine-addicted cancer.

Grant Number: 5R01CA250506-05
NIH Institute/Center: NIH
Principal Investigator: Jin Chen