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Simple Summary: CD8+ CTCL subtypes manifest with widespread clinical, histologic, and phenotypic features that inform the classification of the disease. Through this review, we highlight the importance of utilizing the synergy of clinical, histologic, and immunohistochemical findings to determine a correct diagnosis and applicable treatment plan. Although the vast majority of CTCL subtypes are of the CD4+ T-helper cell differentiation phenotype, there is a spectrum of CD8+ variants that manifest wide-ranging clinical, histologic, and phenotypic features that inform the classification of the disease. CD8, like CD4, and cytotoxic molecules (including TIA and granzyme) are readily detectable via IHC staining of tissue and, when expressed on the phenotypically abnormal T-cell population, can help distinguish specific CTCL subtypes. Nonetheless, given that the histopathologic differential for CD8+ lymphoproliferative disorders and lymphomas may range from very indolent lymphomatoid papulosis (LyP) to aggressive entities like CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (AECTCL), CD8 and/or cytotoxic molecule expression alone is insufficient for diagnosis and is not in itself an indicator of prognosis. We present a review of CTCL subtypes that can demonstrate CD8 positivity: CD8+ mycosis fungoides (MF), LyP type D, subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTL), CD8+ AECTCL, and acral CD8+ T-cell lymphoproliferative disorder (acral CD8+ TCLPD). These diseases may have different clinical manifestations and distinctive treatment algorithms. Due to the rare nature of these diseases, it is imperative to integrate clinical, histologic, and immunohistochemical findings to determine an accurate diagnosis and an appropriate treatment plan. [ABSTRACT FROM AUTHOR]

Recurrence of advanced melanoma after therapy is a major risk factor for reduced survival, and treatment options are limited. Antitumor immune memory plays a critical role in preventing melanoma recurrence and memory T cells could be a potent cell-based therapy, but the identity, and functional properties of the required immune cells are incompletely understood. Here, we show that an IL-7Rhi tumor-specific CD8+ population is critical for antitumor memory and can be epigenetically augmented to drive powerful antitumor immune responses. Using a model of functional antimelanoma memory, we found that high IL-7R expression selectively marks a CD8+ population in lymphoid organs that plays critical roles in maintaining tumor remission after immunotherapy or surgical resection. This population has intrinsic cytotoxic activity, lacks markers of exhaustion and has superior antitumor efficacy. IL-7Rhi cells have a functionally poised epigenetic landscape regulated by DNA methylation, which can be augmented by hypomethylating agents to confer improved survival and complete melanoma clearance in naive mice. Importantly, greater than 95% of tumor-specific T cells in draining lymph nodes after therapy express high levels of IL-7R. This overlap between IL-7Rhi and antigen-specific T cells allows for enrichment of a potent functional CD8+ population without determining antigen-specificity, which we demonstrate in a melanoma model without a known antigen. We identify that IL-7R expression in human melanoma is an independent prognostic factor of improved survival. These findings advance our basic understanding of antitumor memory and suggest a cell-based therapy using high IL-7R expression to enrich for a lymph node population with superior antitumor activity that can be augmented by hypomethylating agents. [ABSTRACT FROM AUTHOR]

Summary Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca 2+ -NFAT signaling and effector functions by repressing sarco/ER Ca 2+ -ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy. [ABSTRACT FROM AUTHOR]