PMID- 22593198
OWN - NLM
STAT- MEDLINE
DCOM- 20120810
LR  - 20220321
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 11
DP  - 2012 Jun 1
TI  - Modulation of microenvironment acidity reverses anergy in human and murine 
      tumor-infiltrating T lymphocytes.
PG  - 2746-56
LID - 10.1158/0008-5472.CAN-11-1272 [doi]
AB  - Stimulating the effector functions of tumor-infiltrating T lymphocytes (TIL) in 
      primary and metastatic tumors could improve active and adoptive T-cell therapies 
      for cancer. Abnormal glycolysis, high lactic acid production, proton 
      accumulation, and a reversed intra-extracellular pH gradient are thought to help 
      render tumor microenvironments hostile to roving immune cells. However, there is 
      little knowledge about how acidic microenvironments affect T-cell immunity. Here, 
      we report that lowering the environmental pH to values that characterize tumor 
      masses (pH 6-6.5) was sufficient to establish an anergic state in human and mouse 
      tumor-specific CD8(+) T lymphocytes. This state was characterized by impairment 
      of cytolytic activity and cytokine secretion, reduced expression of IL-2Ralpha (CD25) 
      and T-cell receptors (TCR), and diminished activation of STAT5 and extracellular 
      signal-regulated kinase (ERK) after TCR activation. In contrast, buffering pH at 
      physiologic values completely restored all these metrics of T-cell function. 
      Systemic treatment of B16-OVA-bearing mice with proton pump inhibitors (PPI) 
      significantly increased the therapeutic efficacy of both active and adoptive 
      immunotherapy. Our findings show that acidification of the tumor microenvironment 
      acts as mechanism of immune escape. Furthermore, they illustrate the potential of 
      PPIs to safely correct T-cell dysfunction and improve the efficacy of 
      T-cell-based cancer treatments.
CI  - (c)2012 AACR
FAU - Calcinotto, Arianna
AU  - Calcinotto A
AD  - Cellular Immunology Unit, San Raffaele Scientific Institute, Milan, Italy.
FAU - Filipazzi, Paola
AU  - Filipazzi P
FAU - Grioni, Matteo
AU  - Grioni M
FAU - Iero, Manuela
AU  - Iero M
FAU - De Milito, Angelo
AU  - De Milito A
FAU - Ricupito, Alessia
AU  - Ricupito A
FAU - Cova, Agata
AU  - Cova A
FAU - Canese, Rossella
AU  - Canese R
FAU - Jachetti, Elena
AU  - Jachetti E
FAU - Rossetti, Monica
AU  - Rossetti M
FAU - Huber, Veronica
AU  - Huber V
FAU - Parmiani, Giorgio
AU  - Parmiani G
FAU - Generoso, Luca
AU  - Generoso L
FAU - Santinami, Mario
AU  - Santinami M
FAU - Borghi, Martina
AU  - Borghi M
FAU - Fais, Stefano
AU  - Fais S
FAU - Bellone, Matteo
AU  - Bellone M
FAU - Rivoltini, Licia
AU  - Rivoltini L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120516
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Interleukin-2)
RN  - KG60484QX9 (Omeprazole)
SB  - IM
MH  - Animals
MH  - *Clonal Anergy
MH  - Female
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Immunotherapy, Adoptive
MH  - Interleukin-2/biosynthesis
MH  - Lymphocyte Activation
MH  - Lymphocytes, Tumor-Infiltrating/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Omeprazole/pharmacology
MH  - *Tumor Microenvironment
EDAT- 2012/05/18 06:00
MHDA- 2012/08/11 06:00
CRDT- 2012/05/18 06:00
PHST- 2012/05/18 06:00 [entrez]
PHST- 2012/05/18 06:00 [pubmed]
PHST- 2012/08/11 06:00 [medline]
AID - 0008-5472.CAN-11-1272 [pii]
AID - 10.1158/0008-5472.CAN-11-1272 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Jun 1;72(11):2746-56. doi: 10.1158/0008-5472.CAN-11-1272. Epub 
      2012 May 16.