Targeting the tumor microenvironment and T cell metabolism for effective cancer immunotherapy

Abstract

The successful implementation of immunotherapies has provided new impetus in the fight against cancer. Antibody‐mediated blockade of immune checkpoint molecules PD‐1/PD‐L1 and CTLA‐4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, while adoptive cell therapies using chimeric antigen receptor‐bearing T cells have proven highly efficacious in B cell leukemia. Furthermore, significant progress has been made in understanding the mechanisms by which tumors evade or become resistant to these immunotherapies. In this regard, approaches to broaden the applicability and enhance the efficacy of immunotherapies increasingly include modulation of tumor and immune cell metabolism. In this mini‐review, we highlight the most recent studies describing novel approaches and targets for the manipulation of the tumor microenvironment and T cell metabolism and describe how these approaches are being combined with current immunotherapies in preclinical studies.

Detecting Early Response to Immune Checkpoint Blockade by Multimodal Molecular Imaging

“…In this study, we investigated the capability of non-invasive metabolic and physiologic imaging to evaluate the early response to ICB therapy in tumor bearing animal models. To our knowledge, this is the first report of metabolic imaging assessment to detect the early response to immune checkpoint blockade therapy using hyperpolarized 13 C MRI.…”

“…Tumor cell necrosis is potentially a more direct biomarker for ICB efficacy. To evaluate necrotic cell death in tumors, hyperpolarized 13 C MRI using [1,[4][5][6][7][8][9][10][11][12][13] C2] fumarate was performed on the same sets of tumors. Fumarate is not actively transported into the cell and the plasma membrane is impermeable to fumarate when intact.…”

“…In this context, it is reported that PD-L1 promotes glycolysis in tumors via Akt/mTOR activation, and that PD-1 blockade can decrease glycolysis in tumors 12 . It is also well known that tumor cells create a challenging environment for the immune system characterized by hypoxia, low pH, high interstitial fluid pressure, and immune-inhibitory metabolites such as lactic acid 13,14 . The impaired perfusion capacity of tumor blood vessels by abnormal tumor vasculature create a highly hypoxic microenvironment, frequently resulting in immune suppression 15 .…”

“…By using 13 C pyruvate as a probe, it is possible to monitor the glycolytic profile of a tumor non-invasively, which has proven useful for monitoring the treatment response to several chemotherapeutics such as anti-angiogenic agent sunitinib and hypoxia-activated prodrug TH-302 22,23 . Similarly, the [1,[4][5][6][7][8][9][10][11][12][13] C2] fumarate probe is expected to detect necrotic tumor cell death in vivo 24,25 .…”

“…Glycolytic flux significantly decreased upon treatment in the less ICB sensitive B16.F10 model but remained essentially unchanged in MC38 tumors. Imaging [1,4-13 C] fumarate conversion to [1,[4][5][6][7][8][9][10][11][12][13] C] malate showed a significant increase in necrosis in the treatment group for the ICB sensitive MC38 tumor (p = 0.0003), with essentially no change in ICB sensitive B16.F10 tumors. Histological assessment showed increased necrotic tissue with enhanced lymphocyte infiltration in the MC38 treatment group, suggesting immunogenic tumor cell death.…”