Cancer Immunology Miniatures

IL17A Blockade Successfully Treated PsoriasiformDermatologic Toxicity from ImmunotherapyDaniel Johnson1, Anisha B. Patel2, Marc I. Uemura1,Van A.Trinh3, Natalie Jackson3,Chrystia M. Zobniw3, Michael T. Tetzlaff4, Patrick Hwu3, Jonathan L. Curry2,4, andAdi Diab3

Abstract

Dermatologic toxicities are the most common immune-related adverse events (irAE) secondary to immune checkpointinhibitors (ICI). First-line treatment for grade 3 or 4 skin irAEsis high-dose corticosteroids, which have their own side effects.Prolonged treatment with corticosteroids may abrogate anti-tumor ICI activity. The cellular causes of these dermatologictoxicities, which can manifest as a variety of clinical presenta-tions, remain unclear. Beyond steroids, recommended treat-

ment options are limited. We report a case of psoriasiformdermatologic toxicity, induced by inhibition of PD-1 with themAb pembrolizumab, which resolved after treatment withsystemic interleukin IL17A blockade. Introduction of IL17Ablockade did not alter the patient's melanoma response topembrolizumab. This case suggests a possible pathogenic roleof Th17 cells the irAE of the skin in this metastatic melanomapatient.

IntroductionImmune checkpoint inhibitors (ICI) have revolutionized can-

cer medicine by improving survival for patients with variousmalignancies (1–6). However, because these mAb agents blocknegative immune regulators, they can disrupt peripheral immunetolerance and cause autoimmune side effects termed immune-related adverse events (irAE; refs. 7, 8). ICI-associated irAEs canaffect almost any organ, but most commonly include dermato-logic toxicities (9, 10). The immune biology of ICI-associatedirAEs is incompletely understood, which limits treatment optionsto broadly immunosuppressive strategies. Consensus guidelinesrecommend treating mild dermatologic irAEs with topical corti-costeroids and moderate or severe cases with systemic corticos-teroids (7, 11–14).

In clinical trials of ICIs, dermatologic toxicities are the mostcommonly reported irAE with an incidence ranging from 25% to30% for monotherapy (anti-CTLA-4 or anti-PD-1/PD-L1) andup to 40% for combination therapy (anti-CTLA-4 and anti-PD-1/PD-L1; refs. 15, 16). In most cases, the reported skin manifesta-tions involve macular rashes and vitiligo. However, moreserious manifestations, such as toxic epidermal necrolysis/

Stevens-Johnson syndrome, bullous pemphigoid, pustular psori-asis, and de novoGrover's disease, have also been reported (17–22).

Here, we report a case of pembrolizumab (PD-1 mAb)–induced psoriasis-like dermatologic toxicity in a patient withadvancedmelanoma. This patient hadno knownprevious clinicalhistory of autoimmune diseases or family history of psoriasis. Thepatient demonstrated a complete skin response to IL17A inhibi-tion (secukinumab) after inadequate benefit from treatment withsystemic corticosteroids.

Materials and MethodsConsents and permissions

All analyses performed and patient information obtained forthis project and other publications referenced in this article wereconducted in accordance to the Declaration of Helsinki, HIPAA,andour institutional guidelines. The patient uponwhom this caseis focused and other patients from referenced case reports havegiven informed consent and consent to publish the clinical detailsthat are contained within this report.

ReagentsIHC studies were performed on the Leica Bond autostainer

with antibodies to the following proteins: CD3 (Agilent Tech-nologies, catalog no. A045201-2, polyclonal, 1:100), CD4(Leica Biotechnologies, catalog no. NCL-L-CD4-368, clone4B12, 1:80), CD8 (Thermo Fisher Scientific, catalog MS-457s,clone C8/144B, 1:100; T-Bet, Cell Signaling Technology, cata-log 13232S, clone D6N8B, 1:100), Gata-3 (Cell SignalingTechnology, catalog no. 5852S, clone D13C9, 1:100), RORgt(Millipore, catalog no. MABF81, clone 6F3.1, 1:800),and phosphor-STAT3 (Tyr705; clone D3A7, Cell SignalingTechnology, catalog no. 9145, 1:100).

Case descriptionAn 80-year-old male presented with stage IIIC cutaneous mel-

anoma of the right scalp and underwent surgical resection in

1Division of Cancer Medicine, University of Texas MD Anderson Cancer Center,Houston, Texas. 2Department of Dermatology, University of TexasMDAndersonCancer Center, Houston, Texas. 3Department of Melanoma Medical Oncology,University of Texas MD Anderson Cancer Center, Houston, Texas. 4Departmentof Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

J.L. Curry and A. Diab contributed equally and are the co-senior authors of thisarticle.

Corresponding Author: Adi Diab, The University of Texas MD Anderson CancerCenter, 1515 Holcombe Blvd, Houston FC3004, TX 77030. Phone: 713-745-7336;E-mail: adiab@mdanderson.org

Cancer Immunol Res 2019;7:860–5

doi: 10.1158/2326-6066.CIR-18-0682

�2019 American Association for Cancer Research.

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March 2015. In September 2015, he developed bilateral lungnodules without other metastatic sites. Biopsy of the right lungconfirmed metastatic melanoma, wild-type for BRAFV600, KIT,andNRAS. Therapywith pembrolizumab (2mg/kg i.v. every threeweeks) was initiated. Twelve weeks after the initial dose ofpembrolizumab, restaging positron emission tomography (PET)imaging showed response of his melanoma to therapy. At thistime, he alsodevelopedmultiple pruritic, erythematous, andwell-demarcated plaques with adherent scales on his back, abdomen,scalp, and bilateral upper/lower extremities without nail changes(Fig. 1). Prior to this, he had no personal history of skin rashes,autoimmune diseases, or family history of autoimmune disease.Hewas treatedwith topical triamcinolone creamandmoisturizerswith minimal symptom relief.

Because of persistent symptoms, pembrolizumab was discon-tinued and dermatology was consulted. A skin biopsy was per-formed that showed histopathologic features consistent with apsoriasiform reaction secondary to pembrolizumab (Fig. 2). Thepatient was subsequently started on oral acitretin (10 mg daily)and a short course of corticosteroids (50 mg prednisone taperedover total of 12 days). The rash improved, but recurred whensteroids were discontinued. Acitretin dose was increased to 25mgdaily, but a severe rash persisted.

Because of persistent rash despite oral acitretin treatment, thepatient started subcutaneous injections of secukinumab (300 mgonce every two weeks), a fully human IL17A mAb, and discon-tinued acitretin. Four weeks after initiation of this therapy, thepatient reported improved pruritus and near clearing of his skin

Figure 1.

Skin exam of the back with erythematous and well-demarcated plaques with adherent scales after therapy with pembrolizumab (A) and resolving after receivingsecukinumab treatment (B).

Figure 2.

Histopathology of psoriasiform-like immune-related adverse event with acanthosis, hyperkeratosis with mounds of parakeratosis and dermal inflammationcomposed predominantly of lymphocytes and neutrophils [inset; hematoxylin and eosin (H&E), 40�, inset, 400�; A]. B,Munro microabscess with collection ofneutrophils in the stratum corneum (H&E, 400�). C,Migration of neutrophils from dermal papilla into the epidermis with mild spongiosis (H&E, 400�).

Psoriasiform Toxicity from CPI Responds to IL17A Blockade

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(Fig. 1). The patient continued secukinumab bi-weekly, but, afterthree treatments, he developed grade 1 thrombocytopenia, aknown toxicity related to secukinumab treatment, which wastherefore discontinued. Initially, our patient had a radiographicpartial response by RECIST 1.1 criteria. However, after discontin-uation of pembrolizumab and initiation of steroids, there was arecurrence of a 1.4-cm metastatic lung nodule. Twenty-eightweeks after secukinumab was administered, this lesion remainedstablewithout reinitiation of pembrolizumab, and the patient didnot develop any new lesions (Fig. 3).

Four weeks after secukinumab was discontinued in October2016, thepatientdevelopedsevere shortnessofbreathattributableto chronic obstructive pulmonary disease exacerbation and vol-ume overload from preexisting and chronic renal failure. Thepatient was hospitalized and passed away shortly thereafter. Nofurther melanoma progression or exacerbation of his skin toxicitywas evident. Formalin-fixed paraffin embedded tissue samplesfromboth thepsoriasiformreactionandpre-pembrolizumab lungmetastasis were analyzed by IHC to assess immune infiltrates.Histologic examination of the skin biopsy demonstrated bothlymphocytic and neutrophil infiltrate in both epidermis anddermis (Fig. 2). Further immunophenotyping showed perivascu-lar infiltrate of CD3þ T cells admixedwith approximately 2:1 ratioof CD4þ T cells and CD8þ T cells, similar to the pre-pembrolizu-mab lung biopsy. Although therewas scattered nuclear expressionof the transcription factors T-Bet [characteristic of type 1 helper Tcells (Th1)] and Gata-3 [characteristic of type 2 helper T cells(Th2)] and essentially negative stains for RORgt [characteristic oftype 17 helper T cells (Th17)] in the tumor immune microenvi-ronment, the inflamed skin tissue had more Gata-3þ cells with asubset exhibitingnuclear expressionofRORgt (Fig.4). Inaddition,the skin lesion appeared to have greater density of cells expressingphosphorylated STAT3 (pSTAT3), another nuclear marker associ-atedwithTh17 cell differentiation (Fig. 4), suggesting the immuneinfiltrate in the skin exhibited greater Th17 differentiation com-pared with the tumor immune infiltrate.

DiscussionThis case illustrates another example of ICI-induced severe

(grade 3 in theCommonTerminologyCriteria for Adverse Events)psoriasiform reaction, an infrequent irAE of the skin. Our patientdeveloped biopsy-proven psoriasiform skin reaction within 12weeks of initiation of pembrolizumab. A few cases of this type ofdermatologic irAE have been reported (19, 21–22), and theunderlying immune biology is not fully understood. Interest hasfocused on the integral role of Th17 and IL17 in the pathogenesisof psoriasis (23, 24). On the basis of two large phase III trials,secukinumab was approved by the FDA in 2015 for patients withmoderate to severe plaque psoriasis (25). Our patient's clinicalhistory and response to secukinumab, together with histologicand immunologic data, suggest that his ICI-induced psoriasiformreaction may have arisen from pathogenesis through theTh17/IL17A axis, like other de novo cases of psoriasis.

Preclinical studies have shown that CD4þ T cells play anessential role in immune toxicity from ICIs. For example,CTLA-4–deficient mice develop an autoreactive lymphoprolifera-tive disorder and die within 3 to 4 weeks of birth (26). Depletionof CD8þ T cells does not alter the onset or severity of this disorder,but CD4þ Th cell depletion prevents this lymphoprolifera-tion (27). Th17 cells, which induce transcription of IL17

Figure 3.

Computerized tomography scan showing a 1.4-cm nodule reappeared 16weeks after steroids were initiated and pembrolizumab was discontinued(A). B, After two doses of secukinumab and pembrolizumab still notreinitiated, nodule remains stable. C, Eleven weeks after secukinumabtreatment was stopped and 28 weeks after pembrolizumab was stopped, thenodule remained stable.

Johnson et al.

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cytokines, are a CD4þ T-cell lineage distinct from Th1/Th2/Tregsubsets that has been implicated in a variety of autoimmunediseases such as rheumatoid arthritis, psoriasis, and inflammatorybowel disease (28, 29). Associations between Th17 cells andIL17 with irAE development from ICIs have been reported. Both

CTLA-4 and PD-1 blockade have been shown to increase periph-eral blood Th17 cell expression in patients with melanoma andprostate cancer (30, 31). One study demonstrated that develop-ment and resolution of immune-related enterocolitis in patientstreated with ipilimumab correlated with fluctuation in serumIL17 (32). These studies suggest that blockade of PD-1/PD-L1 andCTLA-4 can potentiate, in susceptible patients, a Th17-mediatedimmune response, which may induce some types of ICI-associ-ated toxicity.

We sought to identify the predominant lymphocyte subsetswithin the immune infiltrate of our patient's skin toxicity biopsyand tumor biopsy. We found that markers associated with bothTh2 and Th17 immune responses were more predominant in theinflamed skin tissue than in the tumor lymphocyte infiltrate. Inaddition, the predominance of neutrophils supports the role ofIL17 in the pathogenesis of this severe psoriasiform dermatologictoxicity (29). There were limitations to our analysis including theunmatched timing of tumor and skin biopsies (the tumor biopsyoccurred before ICI treatment) and lack of specificity with single-marker IHC for each CD4þ T-cell subtype. More accurate iden-tification of Th17 cells requires multiple markers (such as CD45þ

CD3þ CD8� FOXP3� RORgtþ), which would require multiplexIHC (33).

Our patient had a suboptimal response to systemic corticoster-oids, which are recommended as first-line treatment for grade 3 or4 irAEdermatitis (12–14).Manypatientswith severe irAEs requireprolonged corticosteroid exposure, which causes side effects andmay hinder ICI antitumor activity (34, 35). Some patients do notrespond to the steroids. Inflammatory cytokine blockade, such asby secukinumab, may not only be a useful treatment for steroid-refractory dermatologic irAEs, butmay also be an effective steroid-sparing strategy.

Our group has also treated a different patient who hadadvanced melanoma and concomitant, refractory Crohn diseasewith pembrolizumab and tocilizumab, an IL6 receptor block-er (36). This strategy prevented exacerbation of the patient'sCrohn's disease while allowing her to receive ICI therapy. Treat-ments that specifically target irAE inflammationmay even be usedconcomitantly with immunotherapy to prevent recurrences whenpatients are rechallenged. These strategies need tobeprospectivelyinvestigated in clinical trials.

A deeper understanding of the immune pathogenesis of irAEsmay lead to improved, targeted treatments that do not inhibit theantitumor immune response. Another case has been reported of apatient with pembrolizumab-induced psoriasis flare successfullytreated with secukinumab, although the authors suggested thatthe IL17 blockade led to loss of antitumor efficacy (37). Thisconclusion was based on a biochemical response and subsequentloss of response after introduction of secukinumab in a patientwith mismatch repair–deficient metastatic colorectal cancer, butthere was no radiographic evidence of initial response to pem-brolizumab (37). Results from preclinical studies investigatingthe role of human Th17 cells in antitumor immunity have beenconflicting. Tumor-specific Th17 cells have been shown to bothreduce established B16 melanoma in mouse models throughIFNg production (38, 39) and recruit antitumor effector cellsthrough Th1-type chemokines (40). However, IL17 also has pro-tumor activity through promotion of angiogenesis (41, 42) andpromotion of tumor growth through the IL6–Stat3 pathway (43).Although the contribution of Th17 cells to tumor immunity iscontroversial, manipulation of the IL6/IL23/IL17 axis, which

Figure 4.

IHC studies of the immune infiltrates in psoriasiform-like irAE andmicroenvironment pretreatment lung metastasis were performed usingmAbs against CD3, CD4, CD8, T-bet, Gata-3, RORgt, and pSTAT3. Both skinand lung biopsies exhibited immune infiltrate consisting of CD3þ, CD4þ,CD8þ, and T-Betþ cells. Compared with the tumor microenvironment in thelung biopsy, the composition of immune cells in the psoriasiform-like irAEappeared to exhibit greater Gata-3þ cells with subset positive for RORgt andpSTAT3. (anti-CD3, 400�; anti-CD4, 400�; anti-CD8, 400�; anti-T-Bet,400�; anti-Gata-3, 400�; anti-RORgt, 400�; pSTAT3, 400�).

Psoriasiform Toxicity from CPI Responds to IL17A Blockade

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contributes to chronic inflammation (44–46) as well as tumorgrowth, may be a promising strategy for the treatment of irAEswithout compromising antitumor immunity.

Dermatologic toxicity from ICI therapy is common and itsmanifestations vary. ICI therapy–induced psoriasis is an infre-quent dermatologic irAE, but its development can result in severesymptoms that respond poorly to corticosteroids. IL17A inhibi-tion may represent a more effective, biologic therapy for patientswith psoriasiform reactions from ICI and deserves further study.Our findings, although intriguing, are limited and purely descrip-tive. Studies evaluating the IL6/Th17/IL17 axis as a target touncouple autoimmunity from tumor immunity are warrantedin patients with cancer treated with ICIs.

Disclosure of Potential Conflicts of InterestM.T. Tetzlaff is a consultant/advisory board member for Novartis, Myriad

Genetics, Seattle Genetics. P. Hwu is a consultant/advisory board member forSanofi andGlaxoSmithKline.Nopotential conflicts of interest were disclosed bythe other authors.

Authors' ContributionsConception and design: D.H. Johnson, A. DiabDevelopment of methodology: D.H. Johnson, J.L. Curry, A. DiabAcquisition of data (provided animals, acquired and managed patients,provided facilities, etc.): D.H. Johnson, A.B. Patel, M.I. Uemura, N. Jackson,M.T. Tetzlaff, J.L. Curry, A. DiabAnalysis and interpretation of data (e.g., statistical analysis, biostatistics,computational analysis): D.H. Johnson, M.T. Tetzlaff, P. Hwu, J.L. Curry,A. DiabWriting, review, and/or revision of the manuscript: D.H. Johnson, A.B. Patel,M.I. Uemura, V.A. Trinh, C.M. Zobniw, M.T. Tetzlaff, P. Hwu, J.L. Curry, A. DiabAdministrative, technical, or material support (i.e., reporting or organizingdata, constructing databases): D.H. Johnson, A. Diab

AcknowledgmentsThe University of Texas MD Anderson Cancer Center is supported in part

by the NIH through Cancer Center Support Grant P30CA016672.

Received September 27, 2018; revised January 10, 2019; accepted April 10,2019; published first April 17, 2019.

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2019;7:860-865. Published OnlineFirst April 17, 2019.Cancer Immunol Res   Daniel Johnson, Anisha B. Patel, Marc I. Uemura, et al.   Toxicity from ImmunotherapyIL17A Blockade Successfully Treated Psoriasiform Dermatologic

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Published OnlineFirst April 17, 2019; DOI: 10.1158/2326-6066.CIR-18-0682