PTPN6

Overview

PTPN6 (Protein Tyrosine Phosphatase Non-Receptor Type 6, also known as SHP-1) is a phosphatase that negatively regulates immune cell signaling and B-cell receptor signaling. In cancer genomics, PTPN6 has been identified as both a GCB-selective CRISPR essential dependency in DLBCL and as a component of the TCR/co-stimulatory immunological synapse upregulated on anti-PD-1 therapy in melanoma.

Alterations observed in the corpus

PTPN6 exhibits GCB-selective CRISPR essentiality in a 1001-patient DLBCL genomic cohort, indicating a selective functional dependency in germinal-center B-cell subtype tumors PMID:28985567.
PTPN6 is a component of the TCR/co-stimulatory immunological synapse upregulated on-therapy and enriched in the contraction-phenotype DEG set in metastatic melanoma patients treated with nivolumab PMID:29033130.

Cancer types (linked)

DLBCL: GCB-selective CRISPR essential dependency identified in 1001-patient integrated genomic and CRISPR functional study PMID:28985567.
Melanoma (metastatic): On-therapy upregulation as part of the TCR/co-stimulatory synapse gene set in nivolumab-treated patients PMID:29033130.

Co-occurrence and mutual exclusivity

In DLBCL, PTPN6 shows GCB-selective essentiality, grouping with ZBTB7A, XPO1, and TGFBR2 PMID:28985567.
In melanoma, PTPN6 co-upregulates on-therapy with CTLA4, CD80, CD86, CD28, CD247, CD3D, CD3E, and CD3G PMID:29033130.

Therapeutic relevance

GCB-selective CRISPR essentiality in DLBCL suggests PTPN6/SHP-1 inhibition could be a therapeutic strategy in GCB-subtype lymphomas.
On-therapy upregulation in melanoma immunotherapy contexts indicates a role in immune cell infiltration and TCR signaling activation.

Open questions

The dual role of PTPN6 as a negative regulator (SHP-1) in immune signaling and yet an essential gene in GCB DLBCL warrants further mechanistic investigation.

Sources

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