Phenotypic characterisation of immune cells associated with histological regression in cutaneous melanoma

Abstract

Histological regression and tumour infiltrating lymphocytes represent an early sign of activation of the immune system against primary melanoma. The first phenomenon has been especially discussed in the literature because of its prognostic role, but no clear agreement on its evaluation has been reached. Immunotherapy of advanced stage melanoma has recently shown promising results; an improved understanding of the initial interplay between melanoma cells and the immune system would potentially help tailor treatment for patients. Seventy consecutive melanomas with regression were analysed to identify a prognostic cutoff value of regression extension. Then, we compared the immune infiltrate between regressed and not regressed areas of these regressed melanomas, assessing CD3, CD4, CD8, CD20, CD123, PD1 and FOXP3/CD25 expression. The immune infiltrate of these cases was further compared with 28 control melanomas without regression. A regression extension of 10% represented a reliable cutoff to distinguish two different risk categories in regressed melanomas. Regressed areas were less infiltrated by CD4/ CD25, FOXP3/CD4 or PD1/CD4 compared to not regressed areas of each sample. These lymphocyte subsets are associated with anergy and hamper the immune CD8+ response towards the cancer cells. Moreover, the relevance of these findings was further supported by the observation that not regressed controls were significantly more infiltrated by these anergic immune cell subsets compared to the regressed cases. These results help understand the real meaning of regression in melanoma. Moreover, the association here identified between specific immunomodulatory immune cell subsets and regression could help in developing new therapeutic strategies.

Peritumoral Immune Infiltrate as a Prognostic Biomarker in Thin Melanoma

“…In addition, a high Breslow depth positively correlates with a high number of mitosis, presence of ulceration and less than 10% of regression extension. By corroborating the information in the literature (27,34,35) these results validate the representativeness of patient population analyzed in spite of its limited number.…”

“…Presence of regression was defined as partial, segmental or complete replacement of melanoma cells with a variable host response including dense mononuclear infiltrate, melanophages and/or dermal fibrosis accompanied by increased dermal vascularity, with variable epidermal attenuation ( 24 – 26 ). In addition to further characterize the prognostic role of tumor regression a 10% cut off of regression extension was also adopted as previously reported ( 27 ).…”

Prognostic Value of Intratumoral Lymphocyte-to-Monocyte Ratio and M0 Macrophage Enrichment in Tumor Immune Microenvironment of Melanoma

“…A low lymphocyte count might result in an inadequate immune response in the control of the tumor, which may help to explain why a low lymphocyte:monocyte ratio correlated with poorer OS and increased rates of metastasis, necrosis and Breslow depth at diagnosis. With regard to melanoma, a recent study by Osella-Abate et al demonstrated that increased expression of regulatory T-cell markers, known to be associated with anergy and blunted CD8 T-cell response, led to decreased tumor regression compared with groups that demonstrated decreased regulatory T-cell infiltration [ 44 ]. This suggests that more targeted approaches to specific lymphocyte populations may prove beneficial to achieving melanoma tumor regression.…”

Microenvironment in cutaneous melanomas: a gene expression profile study may explain the role of histological regression

“…Specific subsets of T helper lymphocytes have been identified as associated with anergy and impairment of CD8+ immune response against cancer cells. In particular, the immune infiltrate of regressed melanoma has been proven to have lower counts of CD25+/CD4+, FOXP3+/CD4+ and PD1+/CD4+ lymphocytes compared to the non‐regressed ones 2 …”