Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients

Li, Jing; Srivastava, Raghvendra M.; Ettyreddy, Abhinav; Ferris, Robert L.

doi:10.1186/s40425-015-0097-6

Cited by 46 publications

(39 citation statements)

References 30 publications

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“…The role of anti-EGFR mAbs on myeloid cells in the context of HNSCC is yet undetermined, some studies suggest that panitumumab may mediate ADCC through CD32/FcγRIIa expressed by monocytes (13). Furthermore, recent data suggest that cetuximab may ameliorate suppressive phenotypes of myeloid cells in HNSCC patients (28). However, no significant difference in activation markers on isolated CD14 + monocytes was noted between cetuximab and panitumumab.…”

Section: Discussionmentioning

confidence: 99%

“…In HNSCC patient samples, we noted increased EGFR-positive CTL following treatment with cetuximab, this was not seen in patients treated with panitumumab. Given that recently published data indicated that mDC phenotype and myeloid-derived suppressor cells induction correlated with clinical response to cetuximab, a potential mechanism of myeloid-DC priming may underlie this enhancement of EGFR-specific T cell expansion (28). …”

Section: Discussionmentioning

confidence: 99%

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Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

Trivedi

Srivastava

Concha-Benavente

et al. 2016

Clinical Cancer Research

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113

118

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Purpose EGFR is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates anti-tumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. Experimental Design We measured in vitro activation of cellular components of the innate and adaptive immune system. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. Results Both mAb primarily activate NK cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate ADCC against HNSCC tumor cells, and interestingly, this effect was FcγRIIa and FcγRIIIa genotype dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa), however monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced DC maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared to those treated with panitumumab. Conclusions Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering anti-tumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

Trivedi

Srivastava

Concha-Benavente

et al. 2016

Clinical Cancer Research

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113

118

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“…[26][27][28][29] Tim-3 expression, in response to certain cytokines, has been reported to be induced by activation of the PI3K pathway. 26 We previously showed that pS6 is decreased in TIL after PD-1 stimulation, 30 potentially linking PD-1 to the PI3K-Akt-mTOR pathway. Since TCR/CD28 co-stimulation leads to PI3K/Akt activation, and PD-1 ligation causes inhibition of TCR proximal signaling through SHP-2 27 , leading to decreased PI3K activity, we hypothesized that Tim-3 upregulation after PD-1 blockade might be caused by increased PI3K activity due to de-repression by PD-1 blockade.…”

Section: Tim-3 Upregulation Upon Pd-1 Blockade Requires Activation Ofmentioning

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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“…Immunosuppression in the HNSCC microenvironment is mediated by regulatory T cells (Treg), myeloid derived suppressor cells (MDSC) [3][4][5][6] and dysfunctional or exhausted antitumor effector T cells. During chronic viral infection, exhausted T cells undergo an altered transcriptional program with upregulation of several transcription factors, including Eomes, Blimp-1 and BATF, and downregulation of T-bet.…”

Section: Introductionmentioning

confidence: 99%

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

Shayan

Avery

et al. 2016

OncoImmunology

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Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1 low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1 hi Tim-3 ¡ T cells are actually exhausted. Nonetheless, PD-1 intermed cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.

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Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients

Cited by 46 publications

References 30 publications

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

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

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

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Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients

Cited by 46 publications

References 30 publications

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients

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

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

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