SHP2 Is Overexpressed and Inhibits pSTAT1-Mediated APM Component Expression, T-cell Attracting Chemokine Secretion, and CTL Recognition in Head and Neck Cancer Cells

Leibowitz, Michael S.; Srivastava, Roshni; Filho, Pedro A. Andrade; Egloff, Ann Marie; Wang, Lin; Seethala, Raja R.; Ferrone, Soldano; Ferris, Robert L.

doi:10.1158/1078-0432.ccr-12-1517

Cited by 73 publications

(72 citation statements)

References 43 publications

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“…Because SHP-2 can function as a negative regulator of p-STAT1 in tumor cells (15) and lymphocytes (16), we next investigated whether activation of SHP-2 regulates the inhibitory effects of PD-1 signaling on p-STAT1 and T-bet. To investigate this possibility, we used fusaruside, a small-molecule compound that specifically induces phosphorylation of SHP-2 (16, 25) (Supplemental Figure 3), to activate SHP-2 directly in TIL, bypassing ligand engagement of PD-1.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, SHP-2 inhibitory strategies might be a powerful tool for cancer immunotherapy. Thus, SHP-2 not only suppresses Tc1/Th1 skewing of tumor infiltrating T cells, but also inhibits pSTAT1-dependent expression of HLA/APM (elements of the antigen processing machinery), and secretion of T-cell attracting chemokines RANTES and IP10 (15) and the cytokine IL-12 (unpublished data) by head and neck cancer cells. Therefore, development of a specific SHP-2 inhibitor would be a promising strategy for cancer immunotherapy in the future.…”

Section: Discussionmentioning

confidence: 97%

“…After clustering with the T cell receptor for antigen (TCR) during inflammatory conditions, PD-1 can recruit the phosphatase SHP-2 (15, 16) and relieve SHP-2 from its auto-inhibited state (17). In contrast, blockade of PD-1 signaling inhibits phosphorylation of SHP-2 (18).…”

Section: Introductionmentioning

confidence: 99%

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PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment

et al. 2015

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Immune rejection of tumors is mediated by IFN-γ production and T cell cytolytic activity. These processes are impeded by PD-1, a co-inhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T cell exhaustion marked by decreased proliferation, production of type 1 cytokines and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFN-γ secretion after stimulation of the T cell receptor (TCR), the mechanistic link between PD-1 and its effects on T cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared to peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1 we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1: PD-L1 ligation. We also found that the TCR regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T cell activation and thereby reverse immunosuppression in the tumor microenvironment.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

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PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment

et al. 2015

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“…6 , 23 EGFR overexpression is known to promote immune evasion of malignant cells by inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) while promoting that of STAT3. 24 , 25 Several EGFR-targeted agents are currently available that inhibit oncogenic EGFR signaling, including small-molecule EGFR kinase inhibitors (gefitinib, erlotinib and osimertinib) and antagonistic antibodies (necitumumab, nimotuzumab and cetuximab). Indeed, our results show that gefitinib and erlotinib sensitize cancer cells to apoptosis induction by BIS-1-redirected T cell (Suppl.…”

Section: Discussionmentioning

confidence: 99%

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

et al. 2018

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PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment.To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.

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“…EGFR antagonism can also increase expression of HLA class I expression (14,15) and pro-inflammatory cytokines (16). We have recently shown that SHP2, which operates downstream of EGFR and dephosphorylates p-STAT1, plays an important role in HLA-induced immune escape in HNC (17). Thus, we evaluated if the EGFR-SHP2-STAT1 pathway might regulate HLA downregulation in HNC.…”

Section: Introductionmentioning

confidence: 99%

STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients

Srivastava

Trivedi

Concha-Benavente

et al. 2015

Cancer Immunology Research

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The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies and chromatin immunoprecipitation (ChIP) assays were performed using HNC cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. A prospective phase II clinical trial of neoadjuvant cetuximab was utilized to correlate HLA class I expression with clinical response in HNC patients. EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology-containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression, augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which was abrogated in STAT1−/− cells. Cetuximab enhanced HNC cell recognition by EGFR853–861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271–279). HLA class I upregulation was significantly associated with clinical response in cetuximab-treated HNC patients. EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I downregulation was more prominent in clinical responders to cetuximab therapy, supporting an important role for adaptive immunity in cetuximab antitumor activity. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.

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SHP2 Is Overexpressed and Inhibits pSTAT1-Mediated APM Component Expression, T-cell Attracting Chemokine Secretion, and CTL Recognition in Head and Neck Cancer Cells

Cited by 73 publications

References 43 publications

PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment

PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients

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