Melanoma therapy: Check the checkpoints

Recent mutational and translational studies have revealed that the Ras/Raf/mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression‐free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) is an immune checkpoint molecule that downregulates T‐cell activation by binding to B7 (CD80/CD86) molecules on antigen‐presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T‐cell function by binding to the programmed death‐1 (PD‐1) receptor on T cells. Antibodies against CTLA‐4 and PD‐1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti‐immune checkpoint antibodies in melanoma treatment.     

Treatment and side effect management of CTLA‐4 antibody therapy in metastatic melanoma

Immune‐modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen‐presenting cells and T lymphocytes as an immune response is strongly affected by anti‐CD152 (CTLA‐4)‐antibodies. The cytotoxic T‐lymphocyte (CTLA‐4) receptor binds molecules of the B7‐family which leads to a suppression of T cells. Specific CTLA‐4 antibodies induce an unrestrained T‐cell activation. Treatment with the CTLA‐4 antibodies ipilimumab and tremelimumab has been investigated in metastatic melanoma only within clinical trials. Currently, the critical phase III trial on ipilimumab is in the final analysis process and expected to lead to approval. CTLA‐4 antibodies belong to the most promising new molecules for the treatment of advanced melanoma. During treatment with CTLA‐4 antibodies, distinct adverse events may occur. Treating physicians must be familiar with their appropriate treatment and prophylaxis. The most frequently observed side effects are diseases such as an autoimmune colitis which is typically characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Other autoimmune‐mediated side effects like hypophysitis, hepatitis, iridocyclitis or an exacerbation of lupus nephritis have been reported in the literature. Their early recognition and treatment are mandatory to reduce the risk of sequelae for CTLA‐4‐antibod‐treated patients. Autoimmune‐mediated side effects are reported to correlate positively with treatment response. We review the mechanisms of action, provide an update on clinical trials with the two CTLA‐4‐antibodies for metastatic melanoma, and present detailed recommendations for managing the side effects of these new agents.     

Keratinocytes efficiently process endogenous antigens for cytotoxic T‐cell mediated lysis

Abstract: The generation of a robust CD8⁺ cytotoxic T lymphocyte (CTL) response is a key feature of many immunotherapeutic strategies against epithelial tumors and virally infected epithelial tissue. However, surprisingly few studies have addressed whether primary epithelial cells, expressing defined endogenous antigens, are good targets for CTL‐mediated lysis. Here, we show that primary keratinocytes (KCs), expressing endogenous ovalbumin (OVA) as a transgene, present measurable H‐2K^b/SIINFEKL complexes at the cell surface and are killed by OVA‐specific CTL. Target cell lysis was comparable with a more traditional CTL target cell, EL4, and was enhanced by KC pretreatment with interferon‐γ. These results suggest that primary KCs will be susceptible to CTL‐mediated apoptosis when endogenous KC antigens are targeted during immunotherapy.     

The siRNA‐mediated downregulation of PD‐1 alone or simultaneously with CTLA‐4 shows enhanced in vitro CAR‐T‐cell functionality for further clinical development towards the potential use in immunotherapy of melanoma

Chimeric antigen receptor (CAR)‐T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD‐1) and cytotoxic T lymphocyte–associated protein 4 (CTLA‐4), leading to an impaired antitumor activity. To boost CAR‐T‐cell function, we co‐electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small‐interfering RNAs (siRNAs) to downregulate PD‐1 (siPD‐1) and CTLA‐4 (siCTLA‐4). Flow cytometry revealed that activation‐induced upregulation of both PD‐1 and CTLA‐4 was suppressed when compared to CAR‐T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD‐L1‐ and CD80‐transfected melanoma cells endogenously expressing CSPG4. CAR‐T cells transfected with siPD‐1 alone showed improvement in cytokine secretion. Additionally, CAR‐T cells transfected with either siPD‐1 alone or together with siCTLA‐4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR‐T cells were co‐transfected with siCTLA‐4 only. Taken together, it is feasible to optimize CAR‐T cells by co‐transfection of CAR‐encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR‐T cells, suggesting that this strategy could represent a novel method to enhance CAR‐T‐cell immunotherapy of cancer.     

Management of side effects of immune checkpoint blockade by anti‐CTLA‐4 and anti‐PD‐1 antibodies in metastatic melanoma

CTLA‐4 and PD‐1 are potential targets for tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint‐modifying monoclonal antibodies oppose these effects, inducing T cell‐mediated immune responses to various tumors including melanoma. Both anti‐CTLA‐4 and anti‐PD‐1 antibodies modify the interaction between tumor, antigen‐presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti‐CTLA‐4 antibody ipilimumab as well as the two anti‐PD‐1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune‐mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management.     

Dendritic Cell‐Based Immunotherapy of Malignant Melanoma: Success and Limitations

Dendritic cells (DC) are professional antigen‐presenting cells in the immune system which are able to induce primary T‐cell responses. Because of their central role in the initiation of immune responses, DC are an important tool for tumor‐antigen‐specific immunotherapy of cancer. DC vaccination using tumor‐antigen‐loaded DC has led to tumor regression in individual advanced‐stage cancer patients. However, there is a discrepancy between strong and antigen‐specific T cell responses in vaccinated cancer patients detectable ex vivo and only weak clinical responses. In most cases the immune system of advanced stage IV cancer patients allows only a temporary anti‐tumor response and increasing evidence exists that active suppressive mechanisms of the immune system as well as of the tumor itself ultimately prevent “autoaggressive“ immune reactions against the tumor. Active counter‐regulation of effector T cells by tumor‐antigen‐specific regulatory T‐cell (Treg) populations play a central role in limiting the efficacy of the vaccines. Nevertheless, recent studies have shown that DC,additionally activated byToll‐Like‐receptor ligands (TLRL) can neutralize these suppressive effects of Treg and facilitate the induction of long‐lasting effector T cell responses even in the presence of activated Treg. These studies open a new way for “conditioning“ of DC by TLRL and might significantly enhance the efficiency of DC‐based melanoma vaccines in the future.     

Acneiform primary cutaneous CD4‐positive small/medium pleomorphic T‐cell lymphoma with prominent necrosis

Primary cutaneous CD4‐positive small/medium pleomorphic T‐cell lymphoma (SMPTCL) is an indolent form of cutaneous lymphoma that usually presents in solitary fashion and is histopathologically characterized by nodular infiltration of small‐ to medium‐sized pleomorphic T‐cells. We report the case of a patient who presented with a 5‐year history of acneiform lesions on his face. Histopathologic examination of two lesions revealed a nodular infiltrate of small to medium‐sized lymphocytes with necrosis in the dermis. The proliferating cells were positive for CD2, CD3 and CD4 and negative for CD8, CD30 and CD56. They were positive for TIA‐1 and negative for perforin and granzyme B. The Ki67 proliferation index was approximately 10%. The neoplastic cells expressed programmed death‐1 and lacked expression of CXCL‐13, bcl‐6 and CD10. In situ hybridization for Epstein–Barr virus‐encoded RNA yielded a negative result. T‐cell receptor gene rearrangement showed identical T‐lymphocyte monoclonality in both lesions. In brief, we report a rare case of acneiform SMPTCL with prominent necrosis.     

Role of IL‐10 and TGF‐β in melanoma

IL‐10 and TGF‐β are immunosuppressive cytokines expressed in tumors including melanoma and, therefore, deemed major cause for failing antitumor immune responses. Re‐evaluating their role, we compared their expression by quantitative RT‐PCR in melanoma and skin of healthy individuals, tested their induction in dendritic cells and T cells co‐cultured with tumor cells, and their effects on the immune cells. Both cytokines as well as their receptors were expressed in melanoma at significantly lower levels than in healthy skin. Consequently, the expressions of IL‐10‐responsive SOCS‐3 and TGF‐β‐responsive Smad‐7 were low in tumors but high in healthy skin. T cells co‐cultured with tumor cells developed an anergic state without increased IL‐10 or TGF‐β expression. In vitro tumor‐induced immature dendritic cells produced high IL‐10 levels and less efficiently induced T‐cell proliferation. Nonetheless, they could be induced to mature, and blocking IL‐10 did not alter the capacity of the resulting mature dendritic cells to stimulate T cells. Mature dendritic cells co‐cultured with tumor cells produced increased IL‐10 but decreased TGF‐β and more efficiently induced T‐cell proliferation. The lack of correlation of IL‐10 and TGF‐β with immune deficits in situ and in vitro suggests re‐evaluating their roles in cancer.     

Reduction of skin-homing cytotoxic T cells (CD8+ -CLA+) in patients with vitiligo

Background: Vitiligo is a frequently acquired, hereditary disease, characterized by achromic macules due to the absence of melanocytes. In contrast with earlier studies, in which the main pathogenic role was attributed to anti‐melanocyte antibodies, recent papers have emphasized a role for CD8⁺ cytotoxic T lymphocytes in melanocyte destruction. Fifteen percent of peripheral T cell express cutaneous lymphocyte‐associated antigen (CLA), responsible for skin‐homing T cell. Phototherapy is used to treat patients with generalized vitiligo and it has been shown to interfere with CLA⁺ T cells in other skin diseases. Objective: To describe peripheral blood T cell subpopulations' frequency and ability to express the skin‐homing molecule (CLA) in patients with non‐segmental vitiligo, before and after photochemotherapy (PUVA). Patients and Methods: Twenty‐two patients with generalized and active spreading vitiligo were submitted to 30 PUVA‐8MOP sessions. Lymphocyte immunophenotyping was performed by flow cytometry using anti‐CD3, anti‐CD8 and anti‐CLA monoclonal antibodies. Fifteen healthy volunteers, sex‐ and age‐matched, were included as a control group. Results: CD8⁺–CLA⁺ T cells were significantly reduced in number in untreated vitiligo patients (P=0.008) when compared with control individuals, albeit with a more intense CLA expression (P=0.028). These findings were not altered after PUVA. No significant difference was noticed in CD4/CD8 ratios nor in CD4–CLA⁺ T cell numbers between vitiligo patients and controls, both before and after PUVA. Conclusions: CD8–CLA⁺ T cells are reduced in peripheral blood of patients with non‐segmental vitiligo. This finding may be related to the previously reported increase of CD8⁺ cells in both lesions and perilesional skin of these patients.     

Severe bullous pemphigoid associated with pembrolizumab therapy for metastatic melanoma with complete regression

Bullous pemphigoid (BP) is considered to be a humorally mediated autoimmune disease, but autoreactive T‐cells and T‐regulatory cells (Tregs) have also been implicated in this disease. Tregs and the programmed death‐1 (PD‐1) : programmed death ligand (PD‐L) pathway are both critical in terminating immune response, and elimination of either can result in breakdown of tolerance and development of autoimmunity. We report a patient with metastatic malignant melanoma (MM), who underwent pembrolizumab (anti‐PD‐1) therapy following unsuccessful treatment with ipilimumab [anti‐cytotoxic T‐lymphocyte‐associated protein (CTLA)‐4]. The patient developed BP with increasing serum titres of anti‐BP180 IgG autoantibodies and increasing disease severity during pembrolizumab therapy. High doses of corticosteroids and methotrexate were needed to control the BP. Following the termination of pembrolizumab therapy, imaging showed complete regression of all metastatic sites. This result may indicate a crucial role for T‐cell suppressive activity in controlling and preventing BP.     

1,24‐Dihydroxyvitamin D3 (tacalcitol) prevents skin T‐cell infiltration

Background 1,24‐Dihydroxyvitamin D₃ (tacalcitol), a vitamin D₃ compound, has been used to treat T cell‐mediated inflammatory skin diseases such as psoriasis, prurigo and vitiligo. The best‐known mechanism of action of this compound is inhibition of the abnormal proliferation of keratinocytes and subsequent maturation; however, its effects on skin T‐cell recruitment have not yet been evaluated. Cutaneous lymphocyte‐associated antigen (CLA), a surface glycoprotein expressed on T cells, plays a critical role in skin T‐cell infiltration. We recently reported that 1,25‐dihydroxyvitamin D₃ inhibits skin infiltration of CD4+ T cells by suppressing CLA expression on T cells. Objectives In this study, we investigated the effect of tacalcitol on CLA epitope decoration and on the levels of gut or lymph node homing receptor expression in human T cells. Methods We cultured human T cells with tacalcitol and analysed the effect on CLA expression and skin‐homing ability, and evaluated glycosyltransferase mRNAs. We also performed an in vivo study using an antigen‐dependent delayed‐type hypersensitivity (DTH) mouse model and investigated the effect of tacalcitol on skin‐infiltrating CD4+ T cells. Results Tacalcitol downregulated the expression of CLA and, in parallel, the E‐ and P‐selectin ligand function; however, it exerted no effect on other homing receptors. Subcutaneously and intraperitoneally administered tacalcitol downregulated skin infiltration of effector CD4+ T cells in an in vivo DTH mouse model. Conclusions These findings suggest that tacalcitol reduces skin inflammation by partially downregulating CLA expression levels.     

Side effect management during immune checkpoint blockade using CTLA‐4 and PD‐1 antibodies for metastatic melanoma – an update

CTLA‐4 and PD‐1 play a key role in tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti‐CTLA‐4 and anti‐PD‐1 antibodies affect the interaction between tumor, antigen‐presenting cells and T lymphocytes. Clinical studies of the anti‐CTLA‐4 antibody ipilimumab and the anti‐PD‐1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five‐year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune‐related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.     

IL‐1 signalling determines the fate of skin grafts expressing non‐self protein in keratinocytes

Please cite this paper as: IL‐1 signalling determines the fate of skin grafts expressing non‐self protein in keratinocytes. Experimental Dermatology 2010; 19 : 723–729. Abstract: Although IL‐1 is a known inflammatory cytokine during pathogen infection, the role of IL‐1 in skin graft rejection, particularly where foreign antigen is expressed exclusively in keratinocytes, is less understood. Here, we use a syngeneic skin graft system, where antigens are expressed in epithelial cells via either a keratin 14 or keratin 5 promoter, to explore the role of IL‐1 in graft rejection and induction of epithelial antigen‐specific effector CD8⁺ T‐cell function. Keratin 5 ovalbumin (K5mOVA) transgenic skin grafts destined for rejection demonstrated increased expression of IL‐1β and its receptors compared to K14 HPV16 E7 transgenic grafts that do not reject spontaneously. Rejection of OVA grafts lacking the IL‐1 receptor (IL‐1R1) was delayed and associated with decreased numbers of antigen‐specific CD8 T cells. In contrast, K14E7 grafts survived on immunocompetent, syngeneic recipients with decreased graft levels of IL‐1β and IL‐1R1 and 2. However, in the absence of the IL‐1 receptor antagonist, IL‐1Ra, skin grafts were spontaneously rejected and an E7‐specific CD8 T‐cell response was primed. Thus, expression of the HPV16E7 oncoprotein in epithelial cells prevents IL‐1β‐associated skin graft rejection and induction of antigen‐specific CD8 T‐cell responses. Enhancing IL‐1β signalling, via blocking of the IL‐1 receptor antagonist, may represent an alternative strategy for treatment of HPV16E7‐associated cancers.     

Increased regulatory T‐cell frequencies in patients with advanced melanoma correlate with a generally impaired T‐cell responsiveness and are restored after dendritic cell‐based vaccination

Please cite this paper as: Increased regulatory T‐cell frequencies in patients with advanced melanoma correlate with a generally impaired T‐cell responsiveness and are restored after dendritic cell‐based vaccination. Experimental Dermatology 2010; 19 : e213–e221. Abstract: Naturally occurring CD4⁺ CD25⁺ regulatory T‐cell (Treg) activity is assumed to facilitate tumor development and progression. To elucidate the possible role of Tregs in the course of melanoma progression, we analysed the frequency of Tregs in the peripheral blood of patients at melanoma stages I–IV and in patients at melanoma stage IV that underwent dendritic cell (DC)‐based immunotherapy. Using CD25, Foxp3, CD127 and HLA‐DR as Treg associated markers, we observed increased Treg frequencies in patients at the late melanoma stage (stage IV) when compared to healthy donors. Accumulation of Tregs in patients with progressed melanoma correlated with a general reduction of T‐cell responsiveness to the recall antigens tetanus toxoid and tuberculin‐GT. However, DC‐based immunotherapy not only restored antigen‐specific immunity, but also decreased the frequency of Tregs in peripheral blood of patients with melanoma. These findings indicate that tumor progression in patients with melanoma result in general immunosuppression that is associated with Treg expansion in the periphery and can be overcome by DC‐based vaccination.     

Human T‐lymphotropic virus 1 (HTLV‐1)‐associated lichenoid dermatitis induced by CD8+ T cells in HTLV‐1 carrier,HTLV‐1‐associated myelopathy/tropical spastic paraparesis and adult T‐cell leukemia/lymphoma

Human T‐lymphotropic virus type 1 (HTLV‐1) induces adult T‐cell leukemia/lymphoma (ATLL), HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) and carrier. ATLL is a mature CD4⁺CD25⁺CCR4⁺ T‐cell neoplasm, and approximately half of patients have direct skin involvement manifesting patch, plaque, tumor, multiple papules, erythroderma and purpura. However, there exist secondary eruptions without tumor cell infiltration in patients with ATLL or HAM/TSP and carriers of HTLV‐1. To clarify the presence of reactive skin eruptions in HTLV‐1‐infected individuals, we reviewed our patients with HTLV‐1‐associated diseases. In 2002–2012, we saw 50 ATLL or HAM/TSP patients and HTLV‐1 carriers presenting with skin lesions. We retrospectively selected cases that histologically showed lichenoid tissue reactions with predominant infiltration of CD8⁺ T cells, but not CD4⁺ tumor cells. The cases included erythroderma (HTLV‐1 carrier), lichen planus (HTLV‐1 carrier), alopecia areata (HAM/TSP), chronic actinic dermatitis (HTLV‐1 carrier to acute ATLL conversion) and discoid lupus erythematosus (smoldering ATLL). They were graft‐versus‐host disease‐like, major secondary lesions and seen in HTLV‐1 carriers and patients with HAM/TSP and smoldering ATLL. We coin the term HTLV‐1‐associated lichenoid dermatitis (HALD) to encompass the conditions. HALD may occur in association with the elevated immunity toward HTLV‐1‐infected CD4⁺ T cells, thus sharing the pathogenetic role of cytotoxic T cells with HAM/TSP.     

Enhanced T‐cell activation by immature dendritic cells loaded with HSP70‐expressing heat‐killed melanoma cells

Please cite this paper as: Enhanced T‐cell activation by immature dendritic cells loaded with HSP70‐expressing heat‐killed melanoma cells. Experimental Dermatology 2010; 19: 108–116. Abstract: Vaccination protocols that utilize dendritic cells (DCs) to elicit therapeutic immunity against tumors are the subject of intense research. Given that the capacity of DCs to cross‐present antigens is physiologically low, there is considerable interest to develop strategies that enhance that pathway. In order to best exploit the enhanced cross‐presentation of antigens bound to heat shock protein 70 (HSP70), we analysed melanoma cell preparations for their HSP70 expression. Western blotting revealed strong upregulation of HSP70 after heat‐killing in contrast to UV‐B irradiation. When the uptake of heat‐killed necrotic cells by DCs at various levels of maturation was assessed, 61 ± 7% of immature DCs (iDCs) internalized fluorescence‐labelled necrotic material. Apoptotic material from UV‐B‐irradiated cells was internalized by only 48 ± 5% of iDCs. Maturation‐inducing cytokines did not affect the uptake when added simultaneously with the tumor cell preparations. Loading DCs with heat‐necrotic or apoptotic melanoma cells slightly reduced CD83 expression while leaving CD208 (DC‐LAMP) expression unchanged. As determined by IFN‐γ‐detecting enzyme‐linked‐immunospot assays, iDCs loaded with heat‐killed melanoma cells activated autologous T cells most effectively when used without any further maturation, whereas DCs loaded with apoptotic material required maturation. In conclusion, HSP70‐expressing melanoma cells could be generated by heat‐killing. Loading iDCs with heat‐killed melanoma cells resulted in a superior priming of autologous T cells in vitro.     

Primary cutaneous follicular helper T‐cell lymphoma

Follicular helper T‐cells (TFH) represent a specific subset of CD4‐positive helper T‐cells that help B‐cells to differentiate into long‐lived antibody‐secreting plasma cells or memory B‐cells. The expression of TFH markers in neoplastic T‐cells, traditionally related to the angioimmunoblastic (AITL) subgroup of peripheral T‐cell lymphomas, is nowadays well‐known to be more widespread than previously thought. We report hereby a case of cutaneous T‐cell lymphoma in a 75‐year‐old woman, whose morphological and immunophenotypical features raises the differential diagnosis between cutaneous involvement by AITL and the recently described primary cutaneous T‐cell lymphoma with follicular helper‐phenotype.     

Case of primary cutaneous peripheral T‐cell lymphoma,not otherwise specified,with characteristics of follicular helper T cells

We report a case of an 88‐year‐old woman with a decalvant, erythematous, ulcerated tumor extending from the right temporal to occipital region. Histopathological analysis revealed a dense infiltration of medium‐to‐large‐sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T cells expressed programmed death‐1 (PD‐1), Bcl‐6 and CXCL13. Flow cytometry analysis showed that CD4⁺ PD‐1^hi T cells also expressed CD10, inducible T‐cell co‐stimulator and CXCR5. On the basis of the clinical appearance and the histopathological findings, we diagnosed the patient with primary cutaneous peripheral T‐cell lymphoma, not otherwise specified. Recently, the concept of primary cutaneous follicular helper T (TFH)‐cell lymphoma was proposed, and in this case, tumor cells clearly expressed TFH‐cell markers. Therefore, we considered this case to be a variant of the entity. Although this entity is still provisional, this case supports the new concept.