Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Romero, Ana I.; Chaput, Nathalie; Poirier-Colame, Vichnou; Rusakiewicz, Sylvie; Jacquelot, Nicolas; Chaba, Kariman; Mortier, Erwan; Jacques, Yannick; Caillat‐Zucman, Sophie; Flament, Caroline; Caignard, Anne; Messaoudene, Meriem; Aupérin, Anne; Vielh, Philippe; Dessen, Philippe; Porta, Camillo; Mateus, Christine; Ayyoub, Maha; Valmori, Danila; Eggermont, Alexander M.M.; Robert, Caroline; Zitvogel, Laurence

doi:10.1158/0008-5472.can-13-1186

Cited by 38 publications

(42 citation statements)

References 47 publications

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“…Tumor-associated metalloproteinases induce ligand release, NKG2D engagement, and functional defects (Paschen et al, 2009, Waldhauer and Steinle, 2006). In contrast to stage IV MM (Romero et al, 2014), stage III melanoma maintained high expressions of NKG2D receptors in blood (Figure 4a and data not shown), but such expressions decreased in tumor beds in many patients, a trait relevant for OS (hazard ratio = 0.15 after adjusting for most significant covariates). When combined with BRAF mutation, very high percentages of NKG2D+CD8+ TILs protected against the BRAF mutation-associated dismal prognosis (Figure 4b).…”

Section: Resultsmentioning

confidence: 90%

Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Jacquelot

Roberti

Enot

et al. 2016

Journal of Investigative Dermatology

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Stage III metastatic melanomas require adequate adjuvant immunotherapy to prevent relapses. Prognostic factors are awaited to optimize the clinical management of these patients. The magnitude of metastatic lymph node invasion and the BRAFV600 activating mutation have clinical significance. Based on a comprehensive immunophenotyping of 252 parameters per patient in paired blood and metastatic lymph nodes performed in 39 metastatic melanomas, we found that blood markers were as contributive as tumor-infiltrated lymphocyte immunotypes, and parameters associated with lymphocyte exhaustion/suppression showed higher clinical significance than those related to activation or lineage. High frequencies of CD45RA+CD4+ and CD3-CD56-tumor-infiltrated lymphocytes appear to be independent prognostic factors of short progression-free survival. High NKG2D expression on CD8+tumor-infiltrated lymphocytes, low level of regulatory T-cell tumor-infiltrated lymphocytes, and low PD-L1 expression on circulating T cells were retained in the multivariate Cox analysis model to predict prolonged overall survival. Prospective studies are needed to determine whether such immunological markers may guide adjuvant therapies in stage III metastatic melanomas.

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Section: Resultsmentioning

confidence: 90%

Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Jacquelot

Roberti

Enot

et al. 2016

Journal of Investigative Dermatology

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“…Nevertheless, it is reasonable to hypothesize that neoadjuvant RT in combination with novel systemic agents, such as sorafenib, may improve both local and distant disease-control in patients with STS, potentially through immune-mediated effects. [22, 35]…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

et al. 2014

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Introduction Despite effective local therapy with surgery and radiation (RT), approximately 50% of patients with high grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when anti-angiogenic targeted therapies, such as sorafenib, are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a Phase I/II trial among patients with extremity STS amenable to treatment with curative intent. Methods For the Phase I trial, eight patients with intermediate or high grade STS > 5 cm in maximal dimension or low grade STS > 8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 bid, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during entire period of RT as tolerated. Surgical resection was completed four to six weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the Phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). Results Eight patients were enrolled in the Phase I (5 female, median age 44, 3 high grade pleomorphic, 2 myxoid/round cell liposarcoma, 3 other). Median tumor size was 16 cm (range 8–29), and all tumors were located in the lower extremity. Two of 5 patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and SVT. Radiation toxicity (grade 1 or 2 dermatitis, N=8) and post-surgical complications (3 grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥ 95% tumor necrosis) was observed in 3 patients (38%). Conclusion Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (NCT#00805727, ClinicalTrials.gov)

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“…Immunomonitoring of patients with renal cell carcinoma and melanoma treated with sorafenib failed to evidence modification of pERK1/2 expression in peripheral-blood NK cells after short-term or long-term administration (108). In addition, sorafenib may also positively (Th1) or negatively (DCs) impact other aspects of anti-tumor immunity (61, 109, 110). Whether this action is positive or negative remains to be determinated, as well as the overall “immune benefit” of such antagonistic effects on anti-tumor immunity, besides their direct pro-apoptotic effect on the tumor cell.…”

Section: Targeting Soluble Ligands For Activating Receptorsmentioning

confidence: 99%

Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity

et al. 2014

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Despite evidence of cancer immune-surveillance, which plays a key role in tumor rejection, cancer cells can escape immune recognition through different mechanisms. Thus, evasion to Natural killer (NK) cell-mediated anti-tumor activity is commonly described and is mediated by various mechanisms, mainly cancer cell-induced down-regulation of NK-activating receptors (NCRs, NKG2D, DNAM-1, and CD16) as well as up-regulation of inhibitory receptors (killer-cell immunoglobulin-like receptors, KIRs, NKG2A). Alterations of NK cells lead to an impaired recognition of tumor cells as well as a decreased ability to interact with immune cells. Alternatively, cancer cells downregulate expression of ligands for NK cell-activating receptors and up-regulate expression of the ligands for inhibitory receptors. A better knowledge of the extent and the mechanisms of these defects will allow developing pharmacological strategies to restore NK cell ability to recognize and lyse tumor cells. Combining conventional chemotherapy and immune modulation is a promising approach likely to improve clinical outcome in diverse neoplastic malignancies. Here, we overview experimental approaches as well as strategies already available in the clinics that restore NK cell functionality. Yet successful cancer therapies based on the manipulation of NK cell already have shown efficacy in the context of hematologic malignancies. Additionally, the ability of cytotoxic agents to increase susceptibility of tumors to NK cell lysis has been studied and may require improvement to maximize this effect. More recently, new strategies were developed to specifically restore NK cell phenotype or to stimulate NK cell functions. Overall, pharmacological immune modulation trends to be integrated in therapeutic strategies and should improve anti-tumor effects of conventional cancer therapy.

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Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering

Cited by 38 publications

References 47 publications

Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Immunophenotyping of Stage III Melanoma Reveals Parameters Associated with Patient Prognosis

Phase I Trial of Neoadjuvant Conformal Radiotherapy Plus Sorafenib for Patients with Locally Advanced Soft Tissue Sarcoma of the Extremity

Cancer-Induced Alterations of NK-Mediated Target Recognition: Current and Investigational Pharmacological Strategies Aiming at Restoring NK-Mediated Anti-Tumor Activity

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