Tumor-Infiltrating Lymphocytes and Their Prognostic Value in Cutaneous Melanoma.

Recent breakthroughs in tumor immunotherapy such as immune checkpoint blockade (ICB) antibodies, have demonstrated the capacity of the immune system to fight cancer in a number of malignancies such as melanoma and lung cancer. The numbers, localization and phenotypes of tumor-infiltrating lymphocytes (TIL) are not only predictive of response to immunotherapy but also key modulators of disease progression. In this review, we focus on TIL profiling in cutaneous melanoma using histopathological approaches and highlight the observed prognostic value of the primary TIL subsets. The quantification of TIL in formalin-fixed tumor samples ranges from visual scoring of lymphocytic infiltrates in H&E to multiplex immunohistochemistry and immunofluorescence followed by enumeration using image analysis software. Nevertheless, TIL enumeration in the current literature primarily relies upon single marker immunohistochemistry analyses of major lymphocyte subsets such as conventional T cells (CD3, CD4, CD8), regulatory T cells (FOXP3) and B cells (CD20). We review key studies in the literature on associations between TIL subsets and patient survival. We also cover recent findings with respect to the existence of ectopic lymphoid aggregates found in the TME which are termed tertiary lymphoid structures (TLS) and are generally a positive prognostic feature. In addition to their prognostic significance, the existence of various TIL sub-populations has also been reported to predict a patient's response to ICB. Thus, the literature on the predictive potential of TIL subsets in melanoma patients receiving ICB has also been discussed. Finally, we describe recently developed state-of-the-art profiling approaches for tumor infiltrating immune cells such as digital pathology scoring algorithms (e.g., Immunoscore) and multiplex proteomics-based immunophenotyping platforms (e.g., imaging mass cytometry). Translating these novel technologies have the potential to revolutionize tumor immunopathology leading to altering our current understanding of cancer immunology and dramatically improving outcomes for patients.

IL-32γ potentiates tumor immunity in melanoma.

Myeloid cells orchestrate the antitumor immune response and influence the efficacy of immune checkpoint blockade (ICB) therapies. We and others have previously shown that IL-32 mediates DC differentiation and macrophage activation. Here, we demonstrate that IL-32 expression in human melanoma positively correlates with overall survival, response to ICB, and an immune-inflamed tumor microenvironment (TME) enriched in mature DC, M1 macrophages, and CD8+ T cells. Treatment of B16F10 murine melanomas with IL-32 increased the frequencies of activated, tumor-specific CD8+ T cells, leading to the induction of systemic tumor immunity. Our mechanistic in vivo studies revealed a potentially novel role of IL-32 in activating intratumoral DC and macrophages to act in concert to prime CD8+ T cells and recruit them into the TME through CCL5. Thereby, IL-32 treatment reduced tumor growth and rendered ICB-resistant B16F10 tumors responsive to anti-PD-1 therapy without toxicity. Furthermore, increased baseline IL-32 gene expression was associated with response to nivolumab and pembrolizumab in 2 independent cohorts of patients with melanoma, implying that IL-32 is a predictive biomarker for anti-PD-1 therapy. Collectively, this study suggests IL-32 as a potent adjuvant in immunotherapy to enhance the efficacy of ICB in patients with non-T cell-inflamed TME.