Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature

Abstract

The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan-Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8þ T cells, galectin-macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit.

Pre-existing inflammatory immune microenvironment predicts the clinical response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 vaccination

“…Hence, therapeutic vaccination can incite and modulate inflamed lesions so that the immune infiltration becomes more coordinated and the effector cells increase to similar or higher numbers when compared with healthy vulvar tissue. In this aspect, it does not differ from other T cellbased approaches, including adoptive T cell transfer 38 and checkpoint blockade 10 39 all of which have the best possible clinical impact when a tumor is inflamed or hot before start of therapy. The HPV16 SLP vaccine did not Open access Figure 5 Immune profile of non-responders (NR), partial responders (PR) and complete responders (CR) bases on the relative infiltration of significantly different immune cell subtypes and human papillomavirus (HPV)-specific T cell reactivity.…”

PD-L1/PD-1 expression and tumor-infiltrating lymphocytes in conjunctival melanoma

“…IF staining of CD68 and CD68 + CD163 + showed that the majority of macrophages belong to the M2 phenotype, suggesting a potential tumor-favorable environment created by macrophages in CM. As high cytotoxic T lymphocyte (CTL)/regulatory T cell (Treg) and high M1 (CD68 + CD163 - )/M2 macrophage ratios have been found to be associated with improved survival in breast cancer and cutaneous melanoma, respectively [ 14 , 18 ], we evaluated these ratios in our study. No significant difference in survival or association with clinical parameters was observed ( p > 0.05).…”

Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis

“…32,33 However, almost no study assessed these ratios in melanoma, only one study assessed the prognostic role of CD8/Tregs ratio (Tregs were defined as CD3+ CD8-FOXP3+) HR 1.637 (0.956-2.801) for OS. 60 The last possible explanation for the favorable role of FOXP3+ TILs is that, FOXP3 is not specific for activated Tregs, it is needed to conjoint assess FOXP3 and additional markers, such as CD25. Regretfully, no study assessed this combination in melanoma, only two studies assessed the prognostic role of CD25 for OS by HR 1.8 (no 95% CI) (P= 0.68) 35 and two almost identical survival curves (P= 0.802).…”