Systemic treatment influences on immune accessibility of melanoma: A retrospective histopathological investigation

Background

Major progress has been achieved in immunohistochemical stainings over the last few decades. The latter allowed for studies microscopically analyzing tissue in metastasized melanoma. Aims have been on generally improving understanding in this tumor as well as investigating it's susceptibility for specific treatments. Stainings for PD-1 and PD-L1 are of particular interest as immunotherapies targeting this interaction have recently been approved by the FDA and other relevant authorities. PD-L1 expression as a prognostic factor for survival has been established. However no clear predictive role for subsequent treatments with anti-PD-1 or anti-PD-L1 antibodies was found. We have previously presented preliminary data on the influence of systemic treatments on immune accessibility. This is the final evaluation along with the clinical correlation.

Methods

Pre- and post systemic treatment tumor tissue was stained for multiple markers including CD3, CD8, PD-1, PD-L1 and IDO and analyzed with the focus on changes in lymphocyte distribution under treatment.

Results

In this study, a total of 40 paired metastases pre- and post systemic treatments including both immunotherapies (n = 16) and targeted therapies (n = 25), including multiple treatments per patient, were stained and analyzed. We observe an increase in tumor infiltrating lymphocytes in 15 out of the 40 pairs with a positive trend towards improved survival, whilst in 25 pairs, we observe generally stable lymphocyte infiltration or very small decreases after treatment. Increased infiltration is more often associated with targeted therapy than immunotherapy. Shorter survival in tumors displaying IDO-positive high endothelial venules is confirmed in this study.

Conclusions

Increased tumor lymphocyte infiltration is associated with increased tumor control and can be interpreted as loss of a previous immune privilege of the tumor. The morphological correlate is the redistribution from a previous grenz zone like distribution towards tumor infiltration by lymphocytes and is particularly observed with targeted therapy. Independent from the treatment, IDO-positive endothelial cells are associated with shorter survival.

Clinical trial identification

Legal entity responsible for the study

Ethikkommision des Kantons Zürich

Funding

Zurich University Hospital

Disclosure

All authors have declared no conflicts of interest.