Mechanisms of antitumor immunity by intralesional Mycobacterium bovis Bacillus Calmette-Guerin (BCG) in cutaneous melanoma metastases

LARDONE RICARDO D; CHAN ALFRED; LEE AGNES F; FOSHAG L; FARIES, MARK; SIELING PETER; LEE, DELPHINE J

Portland

Congreso; 2017 Annual Meeting of the Society for Investigative Dermatology; 2017

Society for Investigative Dermatology

Intralesional (IL) therapy using Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been a relatively inexpensive option for treating inoperable cutaneous metastatic melanoma in NCCN guidelines for decades. Mechanisms of IL-BCG used in this manner have not been studied in the skin. We investigated the tumor microenvironment from melanoma patients combined with in vitro studies to further investigate pathways altered by BCG. Since macrophages play a pivotal role in defense against both cancer and mycobacterial infections, we hypothesized BCG can regulate macrophages to promote antitumor immunity. Tumor-associated macrophages (also known as M2) infiltrate solid tumors and impair antitumor immunity. BCG-treated, in vitro-polarized M2 (M2-BCG) show dramatic transcriptional changes involving inflammation, immune cell recruitment, cross-talk and activation pathways. Mechanistic network analysis indicates potential for M2-BCG to improve IFN-γ responses, frequently used as a marker for successful antitumor immunity. Accordingly, we found an increased frequency of IFN-γ-producing CD4+ T cells responding to M2-BCG vs. mock-treated M2 (ppIn vitro BCG-infected cell lines derived from metastatic melanoma patients stimulated a higher frequency of IFN-γ producing-TIL from the same melanoma patient (p < 0.05) than uninfected cell lines. Together, our data suggests BCG promotes an antitumor response in cutaneous metastatic melanoma through indirect and direct effects on the cell types within the tumor microenvironment including macrophages, T cells and the tumor itself.