Jeremy Tchack

Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma

Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs.

Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.

BackgroundAge has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts.MethodsWe queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46–65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis.ResultsWe analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3–6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas.ConclusionsOlder age at time of melanoma diagnosis is associated with shorter MSS, however age’s association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.

Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma. However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination. To date, no biomarker exists that can predict development of irAEs.MethodsWe hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition. Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development.ResultsWe identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group. Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with > 90% accuracy, sensitivity, and specificity. Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNFα signaling, toll-like receptor signaling and microRNA biogenesis.ConclusionsOur results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting.

Association between Ki-67 expression and clinical outcomes among patients with clinically node-negative, thick primary melanoma who underwent nodal staging

Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki‐67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era.

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care

Objectives: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. Methods: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. Results: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. Conclusion: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

Corrigendum to “Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma” (Hum Pathol 2016;57:116-25)

Department of Medicine, New York University School of Medicine, New York, NY, USA 10016 Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016 Department of Population Health, New York University School of Medicine, New York, NY, USA 10016 Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA 10016 Department of Surgery, New York University School of Medicine, New York, NY, USA 10016 Department of Biostatistics, New York University School of Medicine, New York, NY, USA 10016 Department of Pathology, New York University School of Medicine, New York, NY, USA 10016