Deciphering the immune reaction leading to spontaneous melanoma regression: initial role of MHCII+ CD163− macrophages

Abstract

The human cutaneous metastatic melanoma is the deadliest skin cancer. Partial, or less frequently complete spontaneous regressions could be observed, mainly mediated by T cells. Nevertheless, the underlying mechanisms are not fully unraveled. We investigated the first events of the immune response related to cancer regression in Melanoma-bearing Libechov Minipigs (MeLiM), a unique swine model of cutaneous melanoma that regresses spontaneously. Using a multiparameter flow cytometry strategy and integrating new clinical and histological criteria of the regression, we show that T cells and B cells are present only in the late stages, arguing against their role in the initial destruction of malignant cells. NK cells infiltrate the tumors before T cells and therefore might be involved in the induction of the regression process. Myeloid cells represent the main immune population within the tumor microenvironment regardless of the regression stage. Among those, MHCII+ CD163− macrophages that differ phenotypically and functionally compared to other tumor-associated macrophages, increase in number together with the first signs of regression suggesting their crucial contribution to initiating the regression process. Our study supports the importance of macrophage reprogramming in humans to improve current immunotherapy for metastatic melanoma.

Malignant features of minipig melanomas prior to spontaneous regression

“…With an initial CD45 + infiltration of less than 10% and T lymphocytes almost undetected in the early stages of tumor progression, MeLiM melanomas could be considered cold tumors 44 . However, these rapidly growing nodules without inflammation are swiftly infiltrated, with a massive increase in macrophages, and to a lesser extent DC and T lymphocytes, which continue to evolve during regression 21 . The substantial proportion of MeLiM melanoma cells displaying pJNK signal, a pro-inflammatory marker, could drive this infiltration although it may also promote cell survival 45 .…”

“…Longitudinal transcriptional analysis showed that regression is likely due to a combination of immune response and cell-autonomous mechanisms 20 . The immune cell subsets involved in this regression process has recently been characterized emphasizing the dynamic accumulation of different macrophage subtypes and the later infiltration of lymphoid cells 21 . While in the original Czech herd 34% of melanoma-affected minipigs died prematurely 14 , in the French herd only 5.4% died 10 ; therefore, as most MeLiM recover successfully from melanoma, questions remain about the malignancy of these tumors.…”

The cross-talk between macrophages and tumor cells as a target for cancer treatment

“…CD163 enables macrophages to remove erythrocyte debris by binding to haptoglobin. Of note, depletion of CD163 + TAMs resulted in tumor regression in a mouse model of anti-PD-1-resistant melanoma (261)(262)(263)(264). Furthermore, depletion of CD163 + TAMs led to restoration of cytotoxic T-cell and inflammatory monocyte activity, leading to resensitization of tumor cells to anti-PD-1 therapy (265).…”