A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

Chimote, Ameet A.; Gawali, Vaibhavkumar S.; Newton, Hannah S.; Wise‐Draper, Trisha M.; Conforti, Laura

doi:10.3389/fphar.2020.00143

Cited by 16 publications

(15 citation statements)

References 49 publications

(120 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Kv1.3 G was determined from the same trace at +50 mV ( online supplemental figure 1A ) after subtraction of the KCa3.1 current extrapolated by linear regression. 40 The extrapolation method was verified by recording KCa3.1 and Kv1.3 currents via ramp pulse depolarization (as described earlier) before and after perfusion with the specific Kv1.3 blocker ShK-Dap22 (100 nM). 41 Kv1.3 current was determined at +50 mV by subtracting the current remaining after ShK-Dap22 from the current before ShK-Dap22.…”

Section: Methodsmentioning

confidence: 99%

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

Newton

Gawali

Chimote

et al. 2020

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundImmunotherapy has emerged as a promising treatment modality for head and neck squamous cell carcinoma (HNSCC). Pembrolizumab, an anti-programmed death 1 antibody, is an immunotherapy agent currently approved for metastatic HNSCC and curative intent clinical trials. Although clinical responses to pembrolizumab are promising, many patients fail to respond. However, it is well known that T cell cytotoxicity and chemotaxis are critically important in the elimination of HNSCC tumors. These functions depend on ion channel activity and downstream Ca2+ fluxing abilities, which are defective in patients with HNSCC. The purpose of this study was to elucidate the effects of pembrolizumab on potassium (K+) channel (KCa3.1 and Kv1.3) activity, Ca2+ fluxes, and chemotaxis in the cytotoxic T cells of patients with HNSCC and to determine their correlation with treatment response.MethodsFunctional studies were conducted in CD8+ peripheral blood T cells (PBTs) and tumor infiltrating lymphocytes (TILs) from patients with HNSCC treated with pembrolizumab. Untreated patients with HNSCC were used as controls. The ion channel activity of CD8+ T cells was measured by patch-clamp electrophysiology; single-cell Ca2+ fluxing abilities were measured by live microscopy. Chemotaxis experiments were conducted in a three-dimensional collagen matrix. Pembrolizumab patients were stratified as responders or non-responders based on pathological response (percent of viable tumor remaining at resection; responders: ≤80% viable tumor; non-responders: >80% viable tumor).ResultsPembrolizumab increased K+ channel activity and Ca2+ fluxes in TILs independently of treatment response. However, in PBTs from responder patients there was an increased KCa3.1 activity immediately after pembrolizumab treatment that was accompanied by a characteristic increase in Kv1.3 and Ca2+ fluxes as compared with PBTs from non-responder patients. The effects on Kv1.3 and Ca2+ were prolonged and persisted after tumor resection. Chemotaxis was also improved in responder patients’ PBTs. Unlike non-responders’ PBTs, pembrolizumab increased their ability to chemotax in a tumor-like, adenosine-rich microenvironment immediately after treatment, and additionally they maintained an efficient chemotaxis after tumor resection.ConclusionsPembrolizumab enhanced K+ channel activity, Ca2+ fluxes and chemotaxis of CD8+ T cells in patients with HNSCC, with a unique pattern of response in responder patients that is conducive to the heightened functionality of their cytotoxic T cells.

show abstract

Section: Methodsmentioning

confidence: 99%

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

Newton

Gawali

Chimote

et al. 2020

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, pharmacological activation of K Ca 3.1 may enhance antitumor activity of CD8 + T‐cells by overcoming the inhibition of the K Ca 3.1 activity caused by large amounts of adenosine in cancer stroma and/or localized down-regulation of membrane-proximal calmodulin, the Ca 2+ sensor of K Ca 3.1. The diminished association of calmodulin with the channel suppresses the K Ca 3.1 activity in circulating T‐cells and limits their ability to infiltrate adenosine-rich tumor-like microenvironments ( Chimote et al, 2020 ). How NK cells would behave with a K Ca 3.1 activator has not been studied.…”

Section: Therapeutical Approaches and Ion Channels In Pdacmentioning

confidence: 99%

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

et al. 2021

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma is a devastating disease with a dismal prognosis. Therapeutic interventions are largely ineffective. A better understanding of the pathophysiology is required. Ion channels contribute substantially to the “hallmarks of cancer.” Their expression is dysregulated in cancer, and they are “misused” to drive cancer progression, but the underlying mechanisms are unclear. Ion channels are located in the cell membrane at the interface between the intracellular and extracellular space. They sense and modify the tumor microenvironment which in itself is a driver of PDAC aggressiveness. Ion channels detect, for example, locally altered proton and electrolyte concentrations or mechanical stimuli and transduce signals triggered by these microenvironmental cues through association with intracellular signaling cascades. While these concepts have been firmly established for other cancers, evidence has emerged only recently that ion channels are drivers of PDAC aggressiveness. Particularly, they appear to contribute to two of the characteristic PDAC features: the massive fibrosis of the tumor stroma (desmoplasia) and the efficient immune evasion. Our critical review of the literature clearly shows that there is still a remarkable lack of knowledge with respect to the contribution of ion channels to these two typical PDAC properties. Yet, we can draw parallels from ion channel research in other fibrotic and inflammatory diseases. Evidence is accumulating that pancreatic stellate cells express the same “profibrotic” ion channels. Similarly, it is at least in part known which major ion channels are expressed in those innate and adaptive immune cells that populate the PDAC microenvironment. We explore potential therapeutic avenues derived thereof. Since drugs targeting PDAC-relevant ion channels are already in clinical use, we propose to repurpose those in PDAC. The quest for ion channel targets is both motivated and complicated by the fact that some of the relevant channels, for example, KCa3.1, are functionally expressed in the cancer, stroma, and immune cells. Only in vivo studies will reveal which arm of the balance we should put our weights on when developing channel-targeting PDAC therapies. The time is up to explore the efficacy of ion channel targeting in (transgenic) murine PDAC models before launching clinical trials with repurposed drugs.

show abstract

“…↑ migration, chemotaxis [117] melanoma (T lymphocyte) ↑ antitumor immunity in tumor-bearing mice [92,118] head and neck cancer (T lymphocyte) ↑ tumor infiltration [119,120] [125] strong inhibition pKa = 7.35 [126] slight stimulation [127] pancreatic (cell line) ↑ proliferation, migration, contributes to setting the membrane potential [128] KCNK3, KCNK9…”

Section: Ph-dependent Regulation Of Ion Channels In Cancer Cellsmentioning

confidence: 99%

“…If this hypothesis is correct, then it could suggest an overlap with K Ca 3.1, which is adenosine sensitive and required for T cell motility. Along these lines, blockage of K Ca 3.1 could contribute to causing T cell anergy in the acidic pH o [ 119 , 120 , 342 , 343 ].…”

Section: Ph Dependence Of Ion Channels In Tumor Immunitymentioning

confidence: 99%

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology

Pethő¹,

Najder²,

Carvalho

et al. 2020

Cancers

View full text Add to dashboard Cite

Tissue acidosis plays a pivotal role in tumor progression: in particular, interstitial acidosis promotes tumor cell invasion, and is a major contributor to the dysregulation of tumor immunity and tumor stromal cells. The cell membrane and integral membrane proteins commonly act as important sensors and transducers of altered pH. Cell adhesion molecules and cation channels are prominent membrane proteins, the majority of which is regulated by protons. The pathophysiological consequences of proton-sensitive ion channel function in cancer, however, are scarcely considered in the literature. Thus, the main focus of this review is to highlight possible events in tumor progression and tumor immunity where the pH sensitivity of cation channels could be of great importance.

show abstract

A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

Cited by 16 publications

References 49 publications

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology

Contact Info

Product

Resources

About

A Compartmentalized Reduction in Membrane-Proximal Calmodulin Reduces the Immune Surveillance Capabilities of CD8+ T Cells in Head and Neck Cancer

Cited by 16 publications

References 49 publications

PD1 blockade enhances K+channel activity, Ca2+signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

PD1 blockade enhances K+channel activity, Ca2+signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

Ion Channels Orchestrate Pancreatic Ductal Adenocarcinoma Progression and Therapy

pH-Channeling in Cancer: How pH-Dependence of Cation Channels Shapes Cancer Pathophysiology

Contact Info

Product

Resources

About

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer

PD1 blockade enhances K⁺channel activity, Ca²⁺signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer