Mycobacterium bovis Bacillus Calmette-Guérin (BCG) reprograms M2 macrophages to promote antitumor T cell responses

LARDONE, RICARDO D; RAMOS, ROMELA I; NAVARRETE, MARIAN S; TORISU-ITAKURA, HITOE ; FARIES, MARK; SIELING, PETER A; LEE, DELPHINE J

Oklahoma

Congreso; IMMUNOLOGY 2015 Annual Meeting of The American Association of Immunologists; 2015

American Association of Immunologists

M2 Macrophages (MΦs), also known as tumor-associated MΦs, infiltrate solid tumors and impair antitumor immunity. M. bovis Bacille Calmette-Guérin (BCG) is an intralesional (IL) therapy for cutaneous metastatic melanoma (NCCN Guidelines), and induces regression of injected, but also non-injected lesions. Since MΦs play a pivotal role in tumors and mycobacterial infections, we hypothesized that IL-BCG affects tumor regression by altering M2 MΦs. Thus, we investigated the effects of BCG on in vitro polarized M2 MΦs. BCG induced dramatic transcriptional changes in M2 MΦs on genes involving inflammation, immune cell recruitment, cross-talk and activation. To determine whether BCG could alter the classical M2 phenotype, we compared BCG vs mock-treated M2-MΦ cell surface phenotype and response to LPS. BCG-treated M2-MΦ expressed lower CD163 (p<0.01) and secreted less IL-10 (p<0.05), with no effect on IL-12p40, vs mock-treated M2-MΦ. We also investigated the ability of BCG-treated M2-MΦ to activate T cells, and found an increased frequency of IFN-γ producing CD4+ T cells responding to BCG vs mock-treated M2-MΦ (p<0.05), suggesting an adjuvant effect of BCG. Moreover, supernatant from BCG-treated M2-MΦ increased the frequency of granzyme B-producing CD8+ T cells responding to autologous melanoma cell lines (p<0.01). Together, our data indicates IL-BCG therapy could contribute to a tumor-rejecting environment by inducing a reprogramming of M2 MΦs towards a proinflammatory phenotype.