Intratumoral injection of IFN-ß induces chemokine production in melanoma and augments the therapeutic efficacy of anti-PD-L1 mAb.

Despite recent advances in treatment for melanoma patients through using immune checkpoint inhibitors, these monotherapies have limitations and additional treatments have been explored. Type I IFNs have been used to treat melanoma and possess immunomodulatory effects including enhancement of T-cell infiltration. T-cell plays a critical role in immune checkpoint therapies via restoration of effector functions and tumor infiltration by T-cells predicts longer survival in a variety of cancer types. Moreover, tumor-infiltrating T-cells are associated with the expression of chemokines such as CCL5 and CXCR3 ligands in tumor tissues. We therefore investigated whether intratumoral injection of IFN-ß induces the expression of CCL5 and CXCR3 ligands in melanoma cells and has additional antitumor effects when combined with anti-PD-L1 mAb treatment. IFN-ß treatment enhanced CD8+ T-cell infiltration into tumors and CCL5 and CXCR3 ligand expression. In vivo studies using a mouse model showed that monotherapy with IFN-ß, but not with anti-PD-L1 mAb, inhibited tumor growth in comparison to control. However, the therapeutic efficacy of IFN-ß was significantly enhanced by the addition of anti-PD-L1 mAb. This antitumor response of combination therapy was abrogated by anti-CD8 mAb and IFN-ß augmented the neoantigen-specific T-cell response of anti-PD-L1 mAb. Our findings suggest that IFN-ß induces the expression of CCL5 and CXCR3 ligands in melanoma, which could play a role in T-cell recruitment, and enhances the efficacy of anti-PD-L1 mAb treatment in a CD8-dependent manner.

Intratumoral administration of cGAMP transiently accumulates potent macrophages for anti-tumor immunity at a mouse tumor site.

Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45+ CD11bmid Ly6C+ cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8+ T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.

Programmed death-ligand 1 and its soluble form are highly expressed in nasal natural killer/T-cell lymphoma: a potential rationale for immunotherapy.

Nasal natural killer/T-cell lymphoma (NNKTL) is an aggressive neoplasm with poor therapeutic responses and prognosis. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays an important role in immune evasion of tumor cells through T-cell exhaustion. The aim of the present study was to examine the expression of PD-L1 and PD-1 molecules in NNKTL. We detected the expression of PD-L1 in biopsy samples from all of the NNKTL patients studied. PD-L1 was found on both malignant cells and tumor-infiltrating macrophages, while PD-1-positive mononuclear cells infiltrated the tumor tissues in 36% of patients. Most significantly, soluble PD-L1 (sPD-L1) was present in sera of NNKTL patients at higher levels as compared to healthy individuals and the levels of serum sPD-L1 in patients positively correlated with the expression of PD-L1 in lymphoma cells of tumor tissues. In addition, the high-sPD-L1 group of patients showed significantly worse prognosis than the low-sPD-L1 group. Furthermore, we confirmed that membrane and soluble PD-L1 was expressed on the surface and in the culture supernatant, respectively, of NNKTL cell lines. The expression of PD-L1 was observed in tumor tissues and sera from a murine xenograft model inoculated with an NNKTL cell line. Our results suggest that sPD-L1 could be a prognostic predictor for NNKTL and open up the possibility of immunotherapy of this lymphoma using PD-1/PD-L1 axis inhibitors.

Treatment outcome and prognostic factors of tonsillectomy for palmoplantar pustulosis and pustulotic arthro-osteitis: A retrospective subjective and objective quantitative analysis of 138 patients.

Pustulosis palmaris et plantaris (PPP) and pustulotic arthro-osteitis (PAO) are tonsil-related diseases. Treatment outcome of tonsillectomy and prognostic factors influencing the outcome have not been analyzed quantitatively. We evaluated those using the Palmoplantar Pustulosis Area and Severity Index (PPPASI). At 1, 3, 6, 12, 24 and more than 24 months post-tonsillectomy, 20 (31%), 34 (48%), 70 (60%), 57 (80%), 36 (95%) and 23 (96%) patients realized 80% or more improvement of PPP skin lesions, respectively, and eight (17%), 23 (36%), 30 (50%), 38 (79%), 12 (100%) and four (100%) patients showed 80% or more improvement of PPPASI (i.e. PPPASI% ≥ 80%), respectively. At 1, 3, 6, 12 and more than 12 months post-tonsillectomy, 19 (73%), 21 (66%), 27 (73%), 19 (79%) and 15 (83%) patients realized a disappearance of PAO-induced arthralgia, respectively. Kaplan-Meier analysis of 80 patients with PPP revealed that, at 12 and 24 months post-tonsillectomy, lesions disappeared (i.e. PPPASI = 0) in 38% and 66% of patients, respectively, and lesions improved by 80% or more (i.e. PPPASI% ≥ 80%) in 71% and 95% of patients, respectively. The log-rank test and univariate and multivariate analyses showed that smoking cessation post-tonsillectomy and PAO were significant predictive factors for the early disappearance of skin lesions. This report is the first demonstrating objective evidence of the great efficacy of tonsillectomy to improve PPP skin lesions. Even post-tonsillectomy, smoking inhibited the early disappearance of the lesions.

Epigenetic modification augments the immunogenicity of human leukocyte antigen G serving as a tumor antigen for T cell-based immunotherapy.

Tumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4(+) helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8(+) cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G26-40 was effective in eliciting tumor-reactive CD4(+) T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G26-40-specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.

5-Aminolevulinic acid-mediated photodynamic therapy to superficial malignant skin tumors using Super Lizer.

Photodynamic therapy (PDT) using topically applied 5-aminolevulinic acid (ALA) has become a generally accepted treatment modality for superficial malignant skin tumors. However, the costly excimer-dye laser, diode laser and light-emitting diode (LED) frequently used to administrate PDT are impractical to use in most dermatology clinics. This study evaluated the effectiveness of ALA-mediated PDT using a Super Lizer (Tokyo Iken, Tokyo, Japan) equipped with band-pass filters in 38 patients with superficial malignant skin tumors (33 cases of actinic keratosis and five cases of Bowen's disease). Twenty-one cases (18 cases of actinic keratosis and three cases of Bowen's disease) were successfully treated, and the other 17 cases (15 cases of actinic keratosis and two cases of Bowen's disease) showed partial remission after single or repeated administration of PDT. PDT repeated three times at weekly intervals was more effective against actinic keratosis than randomly repeated procedures. The Super Lizer is easy to handle and move, and is less expensive than other known machinery and is useful for PDT in dermatology, especially under the protocol of three times at weekly intervals for the treatment of actinic keratosis.