No abstract

Accurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

No abstract

The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 co-immunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary co-stimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

(1) Melanoma is the most aggressive dermatologic malignancy, with an estimated 106,110 new cases to be diagnosed in 2021. The annual incidence rates continue to climb, which underscores the critical importance of improving the methods to prevent this disease. The interventions to assist with melanoma prevention vary and typically include measures such as UV avoidance and the use of protective clothing, sunscreen, and other chemopreventive agents. However, the evidence is mixed surrounding the use of these and other interventions. This review discusses the heritable etiologies underlying melanoma development before delving into the data surrounding the preventive methods highlighted above. (2) A comprehensive literature review was performed to identify the clinical trials, observational studies, and meta-analyses pertinent to melanoma prevention and incidence. Online resources were queried to identify epidemiologic and clinical trial information. (3) Evidence exists to support population-wide screening programs, the proper use of sunscreen, and community-targeted measures in the prevention of melanoma. Clinical evidence for the majority of the proposed preventive chemotherapeutics is presently minimal but continues to evolve. (4) Further study of these chemotherapeutics, as well as improvement of techniques in artificial intelligence and imaging techniques for melanoma screening, is warranted for continued improvement of melanoma prevention.