Integrated molecular and immunophenotypic analysis of NK cells in anti-PD-1 treated metastatic melanoma patients

Lee, Hansol; Quek, Camelia; Silva, Inês; Tasker, Annie; Batten, Marcel; Rizos, Helen; Lim, Su Yin; Gide, Tuba N.; Shang, Peng; Attrill, Grace H.; Madore, Jason; Edwards, Jarem; Carlino, Matteo S.; Guminski, Alexander; Saw, Robyn P.M.; Thompson, John F.; Ferguson, Peter M.; Palendira, Umaimainthan; Menzies, Alexander M.; Long, Georgina V.; Scolyer, Richard A.; Wilmott, James S.

doi:10.1080/2162402x.2018.1537581

Cited by 70 publications

(74 citation statements)

References 20 publications

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“…This case provided us with an insight that compared with the intravenous pembrolizumab monotherapy, CATAP therapy might be able to tilt the body's immune balance toward enhanced anticancer immune response. This effect might also be reflected by the results on increased NK cells and decreased Tregs in peripheral blood after single cycle of treatment in the combined stage, as both increased NK cells [25,26] and decreased Tregs [27,28] had been reported to correlate with favorable response of immunotherapy in melanoma. 1 3 Although no significant correlations between clinical factors and treatment response were identified, all responders had intrahepatic tumors with maximal diameter less than 5 cm, indicating intrahepatic tumor size could be a potential predictor of response for CATAP therapy.…”

Section: Discussionmentioning

confidence: 93%

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Shen

Chen

et al. 2020

Cancer Immunol Immunother

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Background The presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients. Methods This registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples. Results Of the 15 patients enrolled, no grade 3-4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3-49.0%) and 33.3% (95% CI 2.5-64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5-5.5) and 5.73 (95% CI 1.1-10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells; P = 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells; P = 0.0546) were observed three weeks after the first cycle of treatment in the combined stage. Conclusions The CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.

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Section: Discussionmentioning

confidence: 93%

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Shen

Chen

et al. 2020

Cancer Immunol Immunother

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“…Loss of MHC I expression by tumor cells removes this inhibition, leading to enhanced NK cytotoxicity. Apart from the KIRs, a variety of other inhibitory receptors have been described, which may impact on NK cytotoxicity, including NKG2A, PD-1, T cell immunoreceptor with Ig and ITIM domains (TIGIT), CD96, Siglec-7, and Siglec-9 [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways

Teng

Wang

et al. 2020

Journal of Immunology Research

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Natural killer (NK) cells are innate immune effectors with potent antitumor activity. However, tumor cells can create an immunosuppressive microenvironment to escape immune surveillance. Although accumulating evidence indicates that microenvironmental hypoxia plays an important role in favoring tumor development and immune evasion, it remains unclear by what means hypoxia directly impairs NK cell antitumor activity. In this study, we confirmed that hypoxic NK cells showed significantly lower cytotoxicity against tumor cells. Consistent with this finding, we found that the reduction in NK cell cytotoxicity resulting from hypoxia correlated to the lower expression of granzyme B, IFN-γ, and degranulation marker CD107a, as well as activating receptors including NKp30, NKp46, and NKG2D expressed on the surface of NK cells. More importantly, we further demonstrated that a reduction in the phosphorylation levels of ERK and STAT3 secondary to hypoxia was strongly associated with the attenuated NK cell cytotoxicity. Focusing on the mechanism responsible for reduced phosphorylation levels of ERK and STAT3, we reveal that the activation of protein tyrosine phosphatase SHP-1 (Src homology region 2 domain-containing phosphatase-1) following hypoxia might play an essential role in this process. By knocking down SHP-1 or blocking its activity using a specific inhibitor TPI-1, we were able to partially restore NK cell cytotoxicity under hypoxia. Taken together, we demonstrate that hypoxia could impair NK cell cytotoxicity by decreasing the phosphorylation levels of ERK and STAT3 in a SHP-1-dependent manner. Therefore, targeting SHP-1 could provide an approach to enhance NK cell-based tumor immunotherapy.

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“…NK cells are known to express PD-1 and other checkpoint receptors (45) and their cytotoxic activity in vitro is increased by PD-1 blockade (46). A study on 25 melanoma patients with metastatic disease reported that patients with higher numbers of intra-and peri-tumoral NK cells had higher response rates than those with lower NK cells (47). Previous studies on 40 patients treated with anti-PD-1 also found that responders had higher numbers of CD56 + CD16 + CD69 + NK cells in pretreatment blood samples after activation in vitro (30).…”

Section: Discussionmentioning

confidence: 99%

Pretreatment Innate Cell Populations and CD4 T Cells in Blood Are Associated With Response to Immune Checkpoint Blockade in Melanoma Patients

et al. 2020

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Pirozyan et al. Innate Associations With Checkpoint Responses markers were expressed in practically all patients and the major observation was an increase in CD39 on CD4 T cells during treatment. The results confirm the association of Eomes transcription factor with T cell exhaustion but levels of expression and the ratio with T-bet over Eomes did not differ between the patient groups. Thus, peripheral blood expression of T cell exhaustion markers does not distinguish between responders and non-responders to anti-PD-1 therapy. CD4 T cell expression of IFNγ also differed in pre-treatment samples, indicating that predictors of response unrelated to exhaustion may be present in peripheral blood. The association of response with innate cell populations and CD4 T cell responses requires further study.

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Integrated molecular and immunophenotypic analysis of NK cells in anti-PD-1 treated metastatic melanoma patients

Cited by 70 publications

References 20 publications

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study

Hypoxia Impairs NK Cell Cytotoxicity through SHP-1-Mediated Attenuation of STAT3 and ERK Signaling Pathways

Pretreatment Innate Cell Populations and CD4 T Cells in Blood Are Associated With Response to Immune Checkpoint Blockade in Melanoma Patients

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