Abstract
Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 524-529 |
| Number of pages | 6 |
| Journal | Nature Medicine |
| Volume | 21 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. / Caruana, Ignazio; Savoldo, Barbara; Hoyos, Valentina; Weber, Gerrit; Liu, Hao; Kim, Eugene S.; Ittmann, Michael M.; Marchetti, Dario; Dotti, Gianpietro.
In: Nature Medicine, Vol. 21, No. 5, 01.05.2015, p. 524-529.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes
AU - Caruana, Ignazio
AU - Savoldo, Barbara
AU - Hoyos, Valentina
AU - Weber, Gerrit
AU - Liu, Hao
AU - Kim, Eugene S.
AU - Ittmann, Michael M.
AU - Marchetti, Dario
AU - Dotti, Gianpietro
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
AB - Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
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UR - http://www.scopus.com/inward/citedby.url?scp=84937758074&partnerID=8YFLogxK
U2 - 10.1038/nm.3833
DO - 10.1038/nm.3833
M3 - Article
C2 - 25849134
AN - SCOPUS:84937758074
VL - 21
SP - 524
EP - 529
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -