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Targeting Regulatory T Cells for Cancer Immunotherapy

Fuerst, Mark L.

doi: 10.1097/01.COT.0000508329.83580.01
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NEW YORK—Depletion of naturally occurring regulatory T cells (Treg) by biological or small molecules, along with other treatments to activate effector T cells, such as tumor antigen vaccination or immune checkpoint blockade, can be an effective method of cancer immunotherapy, according to a study presented at the Second lnternational Cancer Immunotherapy Conference “Translating Science Into Survival.”

The depletion of suppression-competent FOXP3 high effector Treg cells from tumor tissues is an effective treatment strategy for various cancers, including colorectal cancer (CRC), noted Shimon Sakaguchi, MD, of Osaka University in Osaka, Japan. “Indeed, depletion of FOXP3-high effector Treg cells alone by administration of cell-depleting anti-CCR4 monoclonal antibody is able to evoke effective tumor immunity without serious autoimmunity,” said Sakaguchi. “Similarly, imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, is able to evoke tumor immunity via specifically depleting effector Treg cells as an off-target effect.”

Treg cells express the transcription factor FOXP3 and are indispensable for immunological self-tolerance and immune homeostasis. “They also hinder effective tumor immunity and can, therefore, be targeted to evoke anti-tumor immune responses by reducing them or attenuating their suppressive activity,” said Sakaguchi.

Human FOXP3+ T cells are heterogeneous in function and phenotype, and include suppressive and non-suppressive populations. Studies to delineate populations of FOXP3+ cells in the peripheral blood have separated out at least three functionally distinct subpopulations.

One population includes the highly proliferative and differentiated FOXP3-high population, which have been designated effector Treg cells, with stable Treg-specific epigenome alterations. The majority of these cells die by apoptosis after suppression, said Sakaguchi.

Another is the naive FOXP3-low population, known as naive Treg cells. In a resting state and upon T cell receptor stimulation, these cells differentiate into effector Treg cells, Sakaguchi said. The third is FOXP3-low non-suppressive population. These cells are unstable in Treg-specific epigenome changes and capable of secreting pro-inflammatory cytokines.

The three FOXP3+ T-cell subpopulations in the peripheral blood can be distinguished by a combination of expression levels of cell surface molecules, such as CD45RA and CD15s. “Each population exhibits distinct behavior in different disease states,” said Sakaguchi.

Evidence is accumulating that abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. The role of Treg cells is controversial in CRCs, in which FOXP3+ T cell infiltration indicates better prognosis in some studies.

“We have recently shown that CRCs, which are commonly infiltrated by terminally differentiated and suppression-competent FOXP3-high Treg cells, can be classified into two types by the degree of additional infiltration of FOX3-low non-suppressive T cells capable of secreting inflammatory cytokines,” said Sakaguchi. “Interestingly, CRCs with abundant infiltration of the latter show significantly better prognosis than those with predominant FOXP3-high Treg cell infiltration.”

Sakaguchi noted that the development of inflammatory FOXP3-low non-Treg cells appears to depend on secretion of IL-12 and transforming growth factor-beta by tumor tissues and to be correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. “Functionally distinct subpopulations of tumor-infiltrating FOXP3+ T cells contribute in opposing ways to determining CRC prognosis,” he said.

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Boosting Immunotherapy in Pancreatic Cancer

Targeting focal adhesion kinase (FAK) may awaken responses to immunotherapy in pancreatic cancer, according to another presentation.

“Immunotherapeutics represent highly promising agents with potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering pancreatic ductal adenocarcinoma (PDAC),” said David G. Denardo, MD, of Washington University School of Medicine in St. Louis, Mo. “This may be due to the presence of a uniquely immunosuppressive tumor microenvironment present in PDACs, which creates a barrier to effective immune surveillance.”

Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiItration and the high numbers of tumor-associated immunosuppressive cells, he said.

Denardo and colleagues have identified hyperactivated FAK activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive tumor microenvironment. “We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration,” said Denardo.

Single-agent FAK inhibition significantly limited tumor progression, resulting in a doubling of survival in a mouse model of human PDAC. “This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells, and immunosuppressive macrophages,” he explained.

“We postulated that these desirable effects of FAK inhibition on the tumor microenvironment might render PDAC tumors more sensitive to immunotherapy,” Denardo said. He and his colleagues found that FAK inhibition rendered a previously unresponsive mouse model to be responsive to anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4 antagonists, leading to a nearly tripling of survival times.

“These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC tumor microenvironment and thus renders tumors responsive to immunotherapy,” concluded Denardo.

Phase I trials are now ongoing to test the effects of FAK inhibition on pancreatic cancer patients.

Mark L. Fuerst is a contributing writer.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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