T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines.

Angela Vasaturo,J Han J.M Van Krieken,Kalijn F Bol,Carl G Figdor,Cornelis J.A Punt,Willeke A.M Blokx,Patricia J.T.A Groenen,I Jolanda M De Vries,Johannes Textor,Altuna Halilovic,Dagmar I Verweij

doi:10.1158/0008-5472.can-15-3211

Abstract

Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3(+) T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P = 0.000026) and a validation cohort of 39 patients (P = 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapy-treated patients was observed for high (P = 0.000566), but not low (P = 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection. Cancer Res; 76(12); 3496-506. ©2016 AACR.

Highlights

The incidence and, to a lesser extent, the mortality of cutaneous melanoma have rapidly increased over the past decades in many countries [1]
We previously demonstrated that skin-infiltrating T cells isolated from delayed-type hypersensitivity (DTH) biopsies strongly correlate with increased survival after dendritic cell (DC) vaccination [24,25,26]
As a simple metric to quantify the strength of T-cell infiltration, we computed the ratio of intratumoral over peritumoral CD3þ T-cell densities (I/P ratio), which is low in weakly infiltrated tumors and high in strongly infiltrated tumors

Summary

Introduction

The incidence and, to a lesser extent, the mortality of cutaneous melanoma have rapidly increased over the past decades in many countries [1]. Metastatic melanoma patients have had a 5-year survival rate of less than 20% [2] and systemic therapy showed only minimal effect [3]. With the currently approved immune checkpoint inhibitors against CTLA-4 and PD-1, 10% to 40% of all metastatic melanoma patients have long-term benefit and survival rates seem to improve [4]. As checkpoint inhibitors are expensive, often induce toxicity, and. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). I.J.M. de Vries contributed to this article

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