Regression Of Melanoma Research Articles

Lower Skin Cancer Risk in Women with Higher Body Mass Index: The Women's Health Initiative Observational Study

The unclear relationship of obesity to incident melanoma and nonmelanoma skin cancer (NMSC) risks was evaluated in the large, geographically diverse longitudinal, prospective Women's Health Initiative (WHI) observational study. Risks of melanoma and NMSC in normal weight women were compared with risks in overweight [body mass index (BMI) = 25-29.0 kg/m(2)] and obese (BMI ≥ 30 kg/m(2)) women, using Cox proportional hazards models for melanoma and logistic regression for NMSC. Over a mean 9.4 years of follow-up, there were 386 melanoma and 9,870 NSMC cases. Risk of melanoma did not differ across weight categories (P = 0.86), whereas in fully adjusted models, NMSC risk was lower in overweight [OR, 0.93; 95% confidence interval (CI), 0.89-0.99] and obese (OR, 0.85; 95% CI, 0.80-0.91) women (P < 0.001). Excess body weight was not associated with melanoma risk in postmenopausal women but was inversely associated with NMSC risk, possibly due to lower sun exposure in overweight and obese women. This supports previous work demonstrating the relationship between excess body weight and skin cancer risk.

Tumoral Melanosis in an Adolescent After Trauma: A Clinicopathological Dilemma

Tumoral melanosis (TM) is a histologic term used to indicate a nodular accumulation of melanophages in the dermis clinically presenting as a pigmented lesion. It is usually associated with regression of melanoma and nonmelanoma melanocytic pigmented lesions. We present the case of a 16-year-old girl with a suspicious pigmented macule on her right knee that appeared after trauma. The lesion was completely excised and diagnosed as TM.

“First AID” for T cell adoptive transfer: TCR affinity maturation by somatic hypermutation

Meeting abstracts Adoptive cell transfer (ACT) of tumor specific T lymphocytes, after host immunodepletion, was shown to mediate objective cancer regression of metastatic melanoma. Effective T cell activation depends, among other factors, on the functional avidity of the peptide-MHC complex (pMHC)

Spontaneous regression of metastatic melanoma – Clinical evidence of the abscopal effect

Metastatic melanoma is poorly understood. Regression of primary lesions has been associated with poor prognosis, but spontaneous regression of all metastatic disease is clearly beneficial. A patient's own immune responses occasionally appear to stimulate spontaneous regression of metastatic disease in melanoma. We present six interesting cases of complete or nearly complete spontaneous regression of metastatic melanoma, suggest possible causes and review the literature. These cases show clear radiological, pathological or clinical evidence of spontaneous regression of metastatic melanoma. This remains a poorly understood phenomena warranting further investigation and may prove useful in the development of immune mediated solutions.

The density and type of MECA‐79‐positive high endothelial venules correlate with lymphocytic infiltration and tumour regression in primary cutaneous melanoma

Tumour-infiltrating lymphocytes have prognostic value in malignant melanoma. High endothelial venules (HEVs) are specialized vessels present in lymph nodes and tertiary lymphoid organs. CCL19, CCL21 and CCR7 regulate lymphocyte migration through HEVs. The aim of our study was to correlate HEV density in cutaneous primary and metastatic malignant melanomas with clinicopathological parameters, and with CCL19, CCL21 and CCR7 mRNA expression. High endothelial venule density was evaluated by immunohistochemistry with a specific antibody, MECA-79, and chemokine expression was evaluated by real-time PCR. MECA-79-positive vessels, covered by cuboidal (C-HEV) or flat (F-HEV) endothelium, were detected in 55% of melanomas. HEV density was higher in primary melanomas than in metastases. Positive correlations were found between C-HEV density and lymphocytic infiltration, and between F-HEV density and tumour regression. Cases in which the number of C-HEVs exceeded that of F-HEVs had higher levels of CCL19, CCL21, and CCR7. Our results support a predominant role for C-HEV in the recruitment of lymphocytes in cutaneous melanomas, mediated by CCL19 and CCL21, whereas the density of F-HEV strongly correlates with tumour regression, Therefore, cuboidal and flat HEVs may serve as indicators of the active and late quiescent phases, respectively, of tumour regression in cutaneous malignant melanoma.

Accuracy of the non-sentinel node risk score (N-SNORE) in patients with cutaneous melanoma and positive sentinel lymph nodes: A retrospective study

Sentinel node (SLN) biopsy in patients with melanoma permits identification of those at risk for further metastases in non-sentinel lymph nodes (NSLN). However, a mere 20% of SLN-positive patients have metastases in NSLN. Therefore we need criteria to predict NSLN-positivity. A new score system known as the non-sentinel risk score, (N-SNORE) based on five clinical and pathological characteristics (gender, regression in primary melanoma, proportion of SNs containing melanoma, perinodal lymphatic invasion, and SN tumor burden), was first published in 2010. In this study, the accuracy of N-SNORE was validated in melanoma patients with positive SLN. A total of 106 melanoma patients with positive SLN, who had undergone complete lymph node dissection (CLND) subsequently, were included in the study. The N-SNORE was calculated in all patients, and the risk was compared to the frequency of NSLN metastases. Statistical analysis of the data was performed. Thirteen patients were at very low risk for NSN metastasis (score 0), 63 patients at low risk (score 1-3), 19 at intermediate risk (score 4-5), 6 at high risk (score 6-7), and 5 at very high risk (score >8). NSLN positivity rates for these 5 risk groups were 7.7%, 18.2%, 21.1%, 33.3%, and 80%, respectively. According to Fisher's exact test, the contingency coefficient was .322; the p-value was .025. An increasing N-SNORE was clearly correlated with a higher risk of NSLN positivity. Based on the p-value and the contingency coefficient, the overall accuracy of the N-SNORE was proven on statistical calculation.

Local Immune Response Predicts Survival in Patients with Thick (T4) Melanomas

Tumor infiltrating lymphocytes (TIL) and histological regression in primary melanoma are generally considered indicators of the local immune response but their roles as prognostic factors have been variably reported. We examined the prognostic role of these variables in patients with high risk (T4) primary melanomas in a large series of patients with long-term follow-up. From a prospectively maintained cohort of patients diagnosed between 1971 and 2004, 161 patients were retrospectively identified with primary thick melanomas (>4mm), no clinical evidence of regional nodal disease (RND) at diagnosis and complete histopathologic data. Univariate and multivariate Cox regression models were performed to identify clinical and histopathologic predictors of disease-specific survival (DSS) and to identify subgroups with differential survival. Factors significantly associated with decreased DSS by univariate analysis included male gender, age ≥60years, axial anatomic location, presence of ulceration, RND, absence of TIL, and presence of regression. In the final multivariate model, TIL and regression, as interacting variables, and RND status remained significantly associated with DSS. In the presence of TIL, concomitant regression was associated with significantly worse survival (p≤0.0001). In the absence of TIL, there was no effect of regression on survival (p=0.324). Primary TIL and regression status and RND status are independently associated with melanoma-specific survival in patients with T4 melanomas; presence of TIL in the primary melanoma with concomitant radial growth phase regression is associated with a poor prognosis and may reflect an ineffective local regional immune response.

CRM1 and BRAF Inhibition Synergize and Induce Tumor Regression in BRAF-Mutant Melanoma

Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival, and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor antitumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276, and KPT-330 were used to induce CRM1 inhibition. Analogs PLX-4720 and PLX-4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell-cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization and retinoblastoma protein (pRb) and survivin modulation. Furthermore, we found that BRAF inhibition abrogates extracellular signal-regulated kinase phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF-mutant and wild-type melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF-mutant melanoma.

Spontaneous Regression of Metastatic Melanoma after Inoculation with Tetanus–Diphtheria–Pertussis Vaccine

Spontaneous regression of metastatic melanoma is an exceedingly rare event, with only 76 well-documented cases in the literature since 1866. Here, we present the case of a patient who developed metastatic melanoma despite interferon therapy and who then achieved spontaneous regression shortly after a reaction to tetanus-diphtheria-pertussis vaccination. A common theme among these cases is the development of febrile illness before remission of the malignant disease. A brief overview of proposed mechanisms for these miraculous recoveries is presented, including a highlight on the potential role of the herv-k-mel viral marker, a nona- or decapeptide that appears in most melanomas, with homologies to peptides in pathogenic microorganisms.

Doppler analysis in regression of uveal melanoma after radioactive plaque

Doppler analysis in regression of uveal melanoma after radioactive plaque

Effect of Melan-Α/Μart-1-peptide vaccination plus IMP321 on antitumor immunity and clinical benefit in patients receiving autologous PBMCs after lymphodepletion.

e20011 Background: Immunotherapy offers great promise for cancer treatmet. Strong evidence supports adoptive cell transfer (ACT) and immunemodulation for regression of advanced melanoma. Few studies assessed the potential synergy between these two strategies. Methods: Twelve patients with metastatic melanoma received multiple Melan-A/Mart-1-peptide vaccinations with (n=6) or without (n=6) IMP321 (LAG-3Ig fusion protein) as an adjuvant in combination with lymphodepleting chemotherapy and ACT. All patients were selected on the basis of ex vivo detectable Melan-A-specific CD8 T cell responses and were immunized at day (D) 0, 8, 15, 22, 28, 52, and 74 post-reinfusion. Results: One-week after reinfusion of bulk autologous PBMCs, a significant expansion of Melan-A-specific CD8 T cells was measured in &gt;83% (n=5) and &lt;17% (n=1) of patients from the IMP321 and control groups, respectively (p=0.02). Compared to the control group, the mean fold increase of Melan-A-specific CD8 T cells was respectively &gt;2-, &gt;4-, and &gt;6-fold higher in the IMP321 group at D15, D30, and D60 (p=0.02). A long-lasting Melan-A-specific CD8 T-cell response was significantly associated with IMP321 (p&lt;0.001). A higher proportion of Melan-A-specific CD8 TEMRA (i.e., CD45RA+CCR7-CD127-) cells was observed in the IMP321 group at the peak of the response (p &lt;0.002), whereas no significant difference was observed in the expression of co-inhibitory receptors (i.e., PD-1, 2B4, TIM3, CD160). IMP321 was associated with a significantly (p&lt;0.04) reduced expansion of regulatory T cells (TREGS); we observed a negative correlation between the fold increase of Melan-A-specific CD8 T cells and the relative expansion of TREGS. Clinical benefit (assessed as CR, PR, and SD) was observed in none of the control patients vs 67% (4/6) of patients from the IMP321 group, (p=0.02). Conclusions: Vaccination with IMP321 as an adjuvant in combination with lymphodepleting chemotherapy and ACT provided clinical benefit and this was associated with a more robust and durable cellular antitumor immune response, supporting further development of IMP321 for future immunotherapeutic strategies. Clinical trial information: NCT00324623.

A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence

In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene-induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically.

BTLA: new biomarker for a highly proliferative CD8+ TIL subset associated with melanoma regression during adoptive cell therapy (P2189)

Abstract Adoptive T cell therapy using tumor-infiltrating lymphocytes (TIL) expanded ex vivo with high-dose IL-2 is a promising approach for the treatment of metastatic melanoma. Recently, our lab demonstrated the importance of CD8+ T cells expressing B and T lymphocyte attentuator (BTLA) with a positive clinical response. This suggests that functional differences may exist between CD8+BTLA+ and CD8+BTLA- cells resulting in the differential therapeutic potency of TIL in treated patients. Here, we isolated BTLA+ and BTLA- CD8+ TIL from metastatic melanoma patients accrued in a Phase II clinical trial at MD Anderson and performed functional assays measuring proliferation, apoptosis, cytokine production, and CTL activity as well as differences in global gene expression profiles between the subsets using microarray analysis. Overall, BTLA appears to be a new and powerful biomarker distinguishing a less differentiated, more highly active and polyfunctional CD8+ T cell subset with high responsiveness to IL-2. As BTLA ligation by its binding partner HVEM (which is expressed on melanoma cells) results in a decreased proliferative responsiveness to anti-CD3 stimulation, paradoxically, BTLA signaling however may still serve as a negative co-inhibitory molecule. Our results also underscore that increased expression of T cell co-inhibitory molecules may not be necessarily markers of “exhaustion”, but markers of more highly-activated, responsive T cells susceptible to negative regulation.

Abstract 2835: Combined stimulation of TLR9 and 4.1BB receptors enhances Trp2 peptide-mediated B16 melanoma regression by increasing Ag-specific CTL activity and infiltration to tumor sites.

Abstract We previously reported that intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) led to the eradication of established B16 melanoma tumors in mice. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigen-specific CD8+ T cell responses against the immunodominant Trp2180-188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. In this study, we observed that when Trp2180-188 self-peptides were combined with the TLR9 agonist, CpG-oligodeoxynucleotide (ODN) for antitumor immune therapy, self-tolerance was broken, giving rise to induction of Trp2-specific CTL responses and some antitumor activity against established melanoma (7 mm in mean diameter). A combination of anti-4.1BB antibodies with Trp2 peptides plus CpG-ODN increased the antitumor regression rate from 0 to 75%. This effect was concomitant with greater induction of Ag-specific CD8+ CTLs and their infiltration into the tumor sites, highlighting the importance of combined stimulation of TLR9 and 4.1BB for achieving tumor eradication. These findings may have implications for designing peptide-based therapeutic vaccines for cancer-patients. Citation Format: Jeong-Im Sin, Hun Mo Ryoo. Combined stimulation of TLR9 and 4.1BB receptors enhances Trp2 peptide-mediated B16 melanoma regression by increasing Ag-specific CTL activity and infiltration to tumor sites. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2013-2835

PO-0984: Value of Doppler ultrasound analysis in the regression of uveal melanoma after episcleral brachytherapy plaque

PO-0984: Value of Doppler ultrasound analysis in the regression of uveal melanoma after episcleral brachytherapy plaque

Immunology of melanoma

It can be safely said that human melanomas are immunogenic. Virtually all the major principles of “tumor immunology” have been experimentally established in this model. It is now amply clear that melanoma cells display multiple antigens and peptide epitopes that are targetable by the host immune system and that patients with melanoma are capable of responding to these antigens and epitopes serologically as well as through the cell-mediated mechanisms. The immune responses against melanoma are, however, subject to regulation by the regulatory processes within the immune system itself and melanoma cells can resort to overt evasive activities. Indeed, the intrinsic as well as the extrinsic mechanisms within the immune system that are designed to control the magnitude as well as the duration of immune responses at times act as constraints against generating a robust and long-lasting antimelanoma response and melanoma cells are capable of using all the tricks (eg, downregulation of targetable molecules, elaboration of immunosuppressive cytokines) available to living organisms so as to evade immune recognition and destruction. As a result, the immune system often fails to protect the host against melanoma development and progression. The cumulative knowledge over the years on melanoma-associated antigens and epitopes, on methods of immunization, and on technologies for generating melanoma antigen-specific T cells, natural or engineered, have led to the development of immunotherapeutic strategies with “melanoma vaccines” and with T-cell–based adoptive immunotherapy for melanoma. Although these strategies have not been uniformly successful in all cases, durable complete regressions of metastatic melanoma can at times be obtained with active specific immunization or adoptive cell therapy. There is reason for hope that continued research in the field is likely to improve the outcome of melanoma immunotherapy: the ultimate goal of tumor immunology.

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

Complete regression of subcutaneous and cutaneous metastatic melanoma with high-dose intralesional interleukin 2 in combination with topical imiquimod and retinoid cream

Immune-Mediated Regression of Established B16F10 Melanoma by Intratumoral Injection of Attenuated Toxoplasma gondii Protects against Rechallenge

Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Because microbes or microbial constituents are powerful adjuvants to stimulate immune responses, we evaluated whether intratumoral administration of a highly immunogenic but attenuated parasite could induce rejection of an established poorly immunogenic tumor. We treated intradermal B16F10 murine melanoma by intratumoral injection of an attenuated strain of Toxoplasma gondii (cps) that cannot replicate in vivo and therefore is not infective. The cps treatment stimulated a strong CD8(+) T cell-mediated antitumor immune response in vivo that regressed established primary melanoma. The cps monotherapy rapidly modified the tumor microenvironment, halting tumor growth, and subsequently, as tumor-reactive T cells expanded, the tumors disappeared and rarely returned. The treatment required live cps that could invade cells and also required CD8(+) T cells and NK cells, but did not require CD4(+) T cells. Furthermore, we demonstrate that IL-12, IFN-γ, and the CXCR3-stimulating cytokines are required for full treatment efficacy. The treatment developed systemic antitumor immune activity as well as antitumor immune memory and therefore might have an impact against human metastatic disease. The approach is not specific for either B16F10 or melanoma. Direct intratumoral injection of cps has efficacy against an inducible genetic melanoma model and transplantable lung and ovarian tumors, demonstrating potential for broad clinical use. The combination of efficacy, systemic antitumor immune response, and complete attenuation with no observed host toxicity demonstrates the potential value of this novel cancer therapy.

Generating Stronger T cells for Adoptive Immunotherapy

Event Abstract Back to Event Generating Stronger T cells for Adoptive Immunotherapy Connie P. Duong1, 2*, Jennifer A. Westwood1, Carmen S. Yong1, 3, Christel Devaud1, Liza B. John1, Phillip K. Darcy1, 3, 4 and Michael H. Kershaw1, 3, 4 1 Peter MacCallum Cancer Centre, Cancer Immunology Program, Australia 2 University of Melbourne, Department of Pathology, Australia 3 University of Melbourne, Sir Peter MacCallum Department of Oncology, Australia 4 Monash University, Department of Immunology, Australia Adoptive immunotherapy mediates effective regression of advanced metastatic melanoma in patients. To target other cancers, we engineered T cells to express chimeric antigen receptors (CARs) empowering them with anti-tumour activity, specifically to the tumor-associated antigen, erbB2. Our current CAR, utilising CD28-CD3ζ signaling domains, although promising, mediates lower activity compared to endogenous TCR responses against foreign antigens. Therefore, we hypothesized that incorporating multiple alternate signaling domains into CARs could result in significantly enhanced anti-tumor responses. To investigate this, we generated a library of approximately 30,000 CARs that incorporated 14 different signaling molecules randomly ligated together directionally and in-frame flanked by SfiI sites and inserted into an anti-erbB2 CAR retroviral vector. The Jurkat T cell line was then retrovirally transduced to express the library and screened for increased CD69 expression or IL-2 secretion in response to antigen specific stimulation. Genomic DNA of selected clones was then extracted, sequenced and cloned into the pSAMEN vector to transduce human peripheral blood mononuclear cells. A diverse range of CARs containing different signaling chains were identified. A particular CAR, containing the tripartite signaling domains DAP10-CD3ζ-CD27 endowed human T cells with the ability to mediate significantly enhanced killing of erbB2+ tumor cells in vitro compared to the CD28-CD3ζ CAR (p<0.05). Strikingly, adoptive transfer of T cells expressing this novel receptor induced significantly increased anti-tumor activity in vivo (p<0.01). In conclusion, it is anticipated that the generation of CARs with novel combinations of signaling domains will lead to stronger T cells for the treatment of cancer. Keywords: immunotherapy of cancer, Chimeric Antigen Receptor, DNA library, Jurkat Cells, genetic modification, CD3 zeta, CD28, DAP10 Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Translational immunology and immune intervention Citation: Duong CP, Westwood JA, Yong CS, Devaud C, John LB, Darcy PK and Kershaw MH (2013). Generating Stronger T cells for Adoptive Immunotherapy. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01120 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Jul 2013; Published Online: 22 Aug 2013. * Correspondence: Ms. Connie P Duong, Peter MacCallum Cancer Centre, Cancer Immunology Program, Melbourne, Australia, connieduong.cd@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Connie P Duong Jennifer A Westwood Carmen S Yong Christel Devaud Liza B John Phillip K Darcy Michael H Kershaw Google Connie P Duong Jennifer A Westwood Carmen S Yong Christel Devaud Liza B John Phillip K Darcy Michael H Kershaw Google Scholar Connie P Duong Jennifer A Westwood Carmen S Yong Christel Devaud Liza B John Phillip K Darcy Michael H Kershaw PubMed Connie P Duong Jennifer A Westwood Carmen S Yong Christel Devaud Liza B John Phillip K Darcy Michael H Kershaw Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Immunosuppression in inflammatory melanoma: can it be resisted by adoptively transferred T cells?

Discovery of tumor antigen (TA) recognized by autologous T cells (TCs) in patients with melanoma has led to clinical protocols using either vaccination or adoptive transfer of TA-specific TCs. However, efficacy of these treatments has been hampered by inhibitory effects exerted on tumor-infiltrating TCs by tumor-intrinsic mediators or by recruitment of immunosuppressive cells. A mouse model of autochthonous melanoma recapitulates some aspects of inflammatory melanoma development in patients. These include a systemic Th2-/Th17-oriented chronic inflammation, recruitment of immunosuppressive myeloid cells and acquisition by tumor-infiltrating TCs of an 'exhausted' phenotype characterized by expression of multiple inhibitory receptors including programmed death-1, also expressed on patients' melanoma-infiltrating TCs. Rather than using extracellular blocking reagents to inhibitory surface molecules on TCs, we sought to dampen negative signaling exerted on them. Adoptively transferred TCs presenting increased cytokine receptor signaling due to expression of an active Stat5 transcription factor were efficient at inducing melanoma regression in the preclinical melanoma model. These transferred TCs thrived and retained expression of effector molecules in the melanoma microenvironment, defining a protocol endowing TCs with the ability to resist melanoma-induced immunosuppression.