NK Cells Control Tumor-Promoting Function of Neutrophils in Mice.

Although natural killer (NK) cells are recognized as direct antitumor effectors, the ability of NK cells to control cancer-associated inflammation, which facilitates tumor progression, remains unknown. In this study, we demonstrate that NK cells control tumor-promoting inflammation through functional modification of neutrophils. NK cells control the tumor-promoting function of neutrophils through an IFNγ-dependent mechanism. Tumor progression in an NK cell-depleted host is diminished when the IL17A-neutrophil axis is absent. In NK cell-depleted mice, neutrophils acquire a tumor-promoting phenotype, characterized by upregulation of VEGF-A expression, which promotes tumor growth and angiogenesis. A VEGFR inhibitor which preferentially suppressed tumor growth in NK cell-depleted mice was dependent on neutrophils. Furthermore, the systemic neutropenia caused by an antimetabolite treatment showed an anticancer effect only in mice lacking NK cells. Thus, NK cells likely control the tumor-promoting and angiogenic function of neutrophils. Cancer Immunol Res; 6(3); 348-57. ©2018 AACR.

IL-17A-producing CD30(+) Vδ1 T cells drive inflammation-induced cancer progression.

Although it has been suspected that inflammation is associated with increased tumor metastasis, the exact type of immune response required to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found that IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated that the length of exposure to an inflammatory microenvironment could be associated with acquiring greater tumorigenicity and that IL-17A was critical for amplifying such local inflammation, as observed in the production of IL-1ß and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23-dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30(+) Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.

Early activation and interferon-γ production of tumor-infiltrating mature CD27 high natural killer cells.

Natural killer (NK) cells are known to be critically involved in the control of tumors through their direct cytotoxic function, but have also been proposed as an initial source of interferon (IFN)-γ that primes subsequent adaptive tumor-specific immune responses. Although mounting evidence supports the importance of NK cells in antitumor immune responses, the immunological characteristics of NK cells infiltrating the tumor microenvironment and the mechanisms that regulate this process remain unclear. In the present study, we found that NK cells infiltrate early developing MCA205 tumors, and further showed that mature CD27(high) NK cells were the predominant subpopulation of NK cells accumulating in the tumor microenvironment. The tumor-infiltrating NK cells displayed an activated cell surface phenotype and provided an early source of IFN-γ. Importantly, we also found that host IFN-γ was critical for NK cell infiltration into the local tumor site and that the tumor-infiltrating NK cells mainly suppressed tumor growth via the IFN-γ pathway. This work implicates the importance of IFN-γ as a positive regulatory factor for NK cell recruitment into the tumor microenvironment and an effective antitumor immune effector response.

Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402.

BACKGROUND: The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma. METHODS: The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays. RESULTS: No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+ gp100-in4+ CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4. CONCLUSION: Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.