Commensal bacteria stimulate antitumor responses via T cell cross-reactivity

Abstract

and Eisai. TAC has served as an advisor for Bristol Myers Squibb, Illumina, Eisai, and An2H. Under a licensing agreement between NexImmune and the Johns Hopkins University, JPS is entitled to shares of royalty received by the university on sales of artificial antigen-presenting cell products described in this article. He also owns NexImmune stock, which is subject to certain restrictions under university policy. JPS is a member of the company's Scientific Advisory Board. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. JPS acknowledges grant funding from AstraZeneca.

Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery

“…In pancreatic cancer, a unique microbiome composition has been observed in patients with longest survival after surgery ( Riquelme et al., 2019 ). Cross-reactive T cells recognizing both tumor antigens and microbial antigens have also been shown to control tumor growth in mouse models ( Bessell et al., 2020 ; Fluckiger et al., 2020 ). In addition, EBV and flu have recently been shown to induce anti-tumor immunity against shared TAAs ( Choi et al., 2020 ; Newman et al., 2020 ).…”

Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors

“…Conversely, tumors expressing the TAA also grew faster in mice lacking Bifidobacterium breve bacterium. 79 Of note, memory immune reactivity against B. longum also correlated with robust CD8 + T cell responses and better prognosis in HBV-related hepatocellular carcinoma patients. 76 The first bacterial species known to harbor "zwitterionic" peptides capable of engaging CD4+ T cell receptors was Bacteroides fragilis.…”

“… 24 A recent study unveiled that the SIY antigen (TAA) of B1610 displayed antigen mimicry with an epitope belonging to Bifidobacterium breve, accounting for the T cell–mediated antitumor responses achieved by oral supplementation with this probiotic. 79 Accordingly, T cells targeting the microbial antigen recognized melanoma tumor cells expressing the SIY tumor-associated antigen. Conversely, tumors expressing the TAA also grew faster in mice lacking Bifidobacterium breve bacterium.…”

Cross-reactivity between cancer and microbial antigens

“… Oral gavage of susceptible (NZW × BXSB)F 1 mice with R. intestinalis induces anti-human β2GPI autoantibodies and lethal thromboses 3 Cancer: Multiple transplantable mouse cancers TSLARFANI contained in the TMP1 protein expressed by an enterococcal phage GSLARFRNI contained in PSMB4 protein Mouse K b Colonization with Enterococcus hirae or Escherichia coli expressing the TMP1 epitope improves control of MCA205 fibrosarcomas 4 Cancer: Lung adenocarcinoma + kidney cancer KLAKFASVV contained in the TMP1 expressed by an enterococcal phage KLQKFASTV contained in GPD1-L protein HLA-A*0201 Cross-reactive T cells found in non-small cell lung cancer patients. Presence of TMP1 associated to good prognosis in patients treated with PD-1 blockade 4 Cancer: melanoma SVYRYYGL expressed by Bifidobacterium breve SIYRYYGL artificially introduced into B16 melanoma cells Mouse K b Colonization with B. breve allows for melanoma control 5 Multiple melanoma antigen-homologous peptides identified by bioinformatics within the human intestinal microbiota EAAGIGILTV present in the MART-1 protein and TLNDECWPA present in MELOE1 HLA-A*0201 In vitro evidence of cross-reactive T cells with defined TCR sequences 4 Inflammatory cardiomyopathy FLILMAALTATFASAQ contained in β-galactosidase from Bacteroides thetaiotaomicron and B. faecis SLKLMATLFSSYATAD from human myosin heavy chain 6 (MYH6) HLA-DQB1* Bacteroides -specific CD4 + T cell and B cell responses found in human myocarditis patients. B. thetaiotaomicron monocolonization expressing the β-galactosidase epitope favors myocarditis development in mice expressing a MYH6- specific T cell receptor on more than 95% of their CD4 + T cells.…”

“…In a pioneering report, Bessel et al demonstrated that a peptide expressed by Bifidobacterium breve can cross-react with a tumor antigen that was artificially induced into B16 melanoma cells. 5 A more recent study from our laboratories demonstrated that a peptide (within the tape measure protein TMP1) encoded by the genome of a 39.2-kb prophage from the Siphoviridae bacteriophage family, which lysogenizes Enterococci , can cross-react with a peptide contained in a natural protein (PSMB4, which is an oncogenic proteasome subunit) expressed by mouse fibrosarcomas and lung cancers. 4 The relevance of this cross-reactivity for tumor control was demonstrated by several lines of evidence, including the observations that (1) only Enterococci harboring the bacteriophage-encoded TMP1 epitope favor immune control of tumors; (2) point mutations of the bacteriophage-encoded TMP1 epitope abolished such an immune control; (3) transfer of the TMP1 epitope into Escherichia coli conferred antitumor immunity-inducing properties to this usually inert bacterium if it was orally administered to mice; (4) mutation of the PSMB4 epitope in tumor cells rendered them resistant to TMP1-encoding bacteriophage-elicited immunosurveillance.…”