Tumor-infiltrating Tim-3<sup>+</sup> T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

Li, Jing; Shayan, Gulidanna; Avery, Lyndsay; Jie, Hyun Bae; Gildener-Leapman, Neil; Schmitt, Nicole C.; Lü, Bin; Kane, Lawrence P.; Ferris, Robert L.

doi:10.1080/2162402x.2016.1200778

Cited by 45 publications

(40 citation statements)

References 40 publications

(56 reference statements)

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“…As PD-1 has been shown to negatively regulate T cell phenotype, proliferation and instead induces apoptosis (13,14,28), the combination of our observations linking PD-1 and peripheral effector memory subsets in vivo supports the association of PD-1 with clonally expanded, tumor-reactive populations (11). In this situation ligation of PD-1 by its ligands is likely, and even more so for the PD-1 high expressing populations.…”

Section: Discussionsupporting

confidence: 77%

“…On the other hand, PD-1 positivity has been shown to represent antigen experienced, TA-specific T cells (11) and has been correlated with better clinical outcome (12). Additionally, other checkpoint receptors such as T cell immunoglobulin-3 (Tim-3) (13,14), Lymphocyte activation gene-3 (LAG-3) and B and T lymphocyte attenuator (BTLA) are under investigation. Tim-3 has been identified as a specific marker of fully differentiated IFN-γ producing CD4 + and CD8 + T cells (15).…”

Section: Introductionmentioning

confidence: 99%

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PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

et al. 2017

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Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV− patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

et al. 2017

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“…1). Thus, PD-1 C Tim-3 C T cells appeared to be the most dysfunctional HNSCC TIL subset, 18,20 and the expression of Tim-3 correlates with more prominent defects in functionality to single positive PD-1 C cells. These results raised the question of whether, and how, co-expression of Tim-3 might be modulated in response to blockade of the PD-1 pathway, which suffers from a relatively low single-agent response rate.…”

Section: Tim-3mentioning

confidence: 99%

“…C T cells, [15][16][17][18] and concurrent Tim-3 blockade appears to enhance the effects of anti-PD-1 mAbs in restoring T cell functionality. 19 However, dynamic changes in Tim-3 expression and signaling during the response to anti-PD-1 treatment, including potential signaling cross-talk in exhausted TIL, have not been investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

et al. 2016

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Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL. We observed that PD-1 and Tim-3 coexpression was associated with a more exhausted phenotype, with the highest PD-1 levels on TIL coexpressing Tim-3. Dampened Akt/S6 phosphorylation in these PD-1 C Tim-3 C TIL, when the PD-1 pathway was ligated, suggested that signaling cross-talk could lead to escape through Tim-3 expression. Indeed, PD-1 blockade of human HNSCC TIL led to further Tim-3 upregulation, supporting a circuit of compensatory signaling and potentially permitting escape from anti-PD-1 blockade in the tumor microenvironment. Also, in a murine HNC tumor model that is partially responsive to anti-PD-1 therapy, Tim-3 was upregulated in TIL from persistently growing tumors. Significant antitumor activity was observed after sequential addition of anti-Tim-3 mAb to overcome adaptive resistance to anti-PD-1 mAb. This increased Tim-3-mediated escape of exhausted TIL from PD-1 inhibition that was mediated by phospho-inositol-3 kinase (PI3K)/Akt complex downstream of TCR signaling but not cytokine-mediated pathways. Taken together, we conclude that during PD-1 blockade, TIL upregulate Tim-3 in a PI3K/Aktdependent manner, providing further support for dual targeting of these molecules for more effective cancer immunotherapy.

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“…Blockade of TIM-3 can increase cytokine production, including IFNγ and TNFα production, enhance expansion of tumor antigen NY-ESO-1–specific CD8 + T cells upon antigen stimulation, and act synergistically when combined with PD-1 blockade (13). Thus, blockade of TIM-3 has therapeutic potential in treating cancer patients by impairing the antitumor activities of tumor antigen-specific CD8 + TILs (14, 15). …”

Section: Introductionmentioning

confidence: 99%

Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients

Jie

Srivastava

Argiris

et al. 2017

Cancer Immunology Research

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Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients.

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Tumor-infiltrating Tim-3⁺ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

Cited by 45 publications

References 40 publications

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients

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Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

Cited by 45 publications

References 40 publications

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients

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Product

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Tumor-infiltrating Tim-3⁺ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk