Journal Articles

Cancer Immunobiology

Basic research studies that extend knowledge in the field of cancer immunotherapy

Immunotherapy resistance by inflammation-induced dedifferentiation

More

A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T cell transfer therapy (ACT) to the MART-1 antigen, a phenomenon that had only been observed in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART-1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART-1 T-cell receptor expressing T cells or with TNFalpha, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.

Author Info: (1) David Geffen School of Medicine, University of California Los Angeles. (2) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (3) University

Author Info: (1) David Geffen School of Medicine, University of California Los Angeles. (2) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (3) University of California Los Angeles. (4) Department of Molecular and Medical Pharmacology, University of California Los Angeles. (5) Surgical Oncology, University of California Los Angeles. (6) Hematology and Oncology, University of California Los Angeles. (7) Path & Lab Med-Anatomic Path, University of California Los Angeles. (8) 54-140 CHS, University of California Los Angeles. (9) Oncology, BioGraph 55, Inc. (10) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (11) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles aribas@mednet.ucla.edu.

Less

Large-scale database mining reveals hidden trends and future directions for cancer immunotherapy

More

Cancer immunotherapy has fundamentally changed the landscape of oncology in recent years and significant resources are invested into immunotherapy research. It is in the interests of researchers and clinicians to identify promising and less promising trends in this field in order to rationally allocate resources. This requires a quantitative large-scale analysis of cancer immunotherapy related databases. We developed a novel tool for text mining, statistical analysis and data visualization of scientific literature data. We used this tool to analyze 72002 cancer immunotherapy publications and 1469 clinical trials from public databases. All source codes are available under an open access license. The contribution of specific topics within the cancer immunotherapy field has markedly shifted over the years. We show that the focus is moving from cell-based therapy and vaccination towards checkpoint inhibitors, with these trends reaching statistical significance. Rapidly growing subfields include the combination of chemotherapy with checkpoint blockade. Translational studies have shifted from hematological and skin neoplasms to gastrointestinal and lung cancer and from tumor antigens and angiogenesis to tumor stroma and apoptosis. This work highlights the importance of unbiased large-scale database mining to assess trends in cancer research and cancer immunotherapy in particular. Researchers, clinicians and funding agencies should be aware of quantitative trends in the immunotherapy field, allocate resources to the most promising areas and find new approaches for currently immature topics.

Author Info: (1) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Site, German Cancer Consortium (DKTK)

Author Info: (1) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Site, German Cancer Consortium (DKTK), Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (2) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Unit for Experimental Oncology Therapy, Thoraxklinik, University of Heidelberg, Heidelberg, Germany. (3) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (4) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (5) Department of Electrical and Electronic Engineering, School of Mathematics, Computer Science and Engineering, City, University of London, London, UK. (6) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (7) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (8) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Site, German Cancer Consortium (DKTK), Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany. (9) Department of Medical Oncology and Internal Medicine VI, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Heidelberg Site, German Cancer Consortium (DKTK), Heidelberg, Germany. Clinical Cooperation Unit Applied Tumor Immunity, D120, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Less

Increase in PD-L1 expression after pre-operative radiotherapy for soft tissue sarcoma

More

Soft tissue sarcomas (STS) have minimal expression of PD-L1, a biomarker for PD-1 therapy efficacy. Radiotherapy (RT) has been shown to increase PD-L1 expression pre-clinically. We examined the expression of PD-L1, pre- and post-RT, in 46 Stage II-III STS patients treated with pre-operative RT (50-50.4 Gy in 25-28 fractions) followed by resection. Five additional patients who did not receive RT were utilized as controls. PD-L1 expression on biopsy and resection samples was evaluated by immunochemistry using the anti PD-L1 monoclonal antibody (E1L3 N clone; Cell Signaling). Greater than 1% membranous staining was considered positive PD-L1 expression. Changes in PD-L1 expression were analyzed via the Fisher exact test. Kaplan-Meier statistics were used to correlate PD-L1 expression to distant metastases (DM) rate. The majority of STS were T2b (87.0%), high-grade (80.4%), undifferentiated pleomorphic histology (71.7%), and originated from the extremities (84.6%). Zero patients demonstrated PD-L1 tumor expression pre-RT. Post-RT, 5 patients (10.9%) demonstrated PD-L1 tumor expression (p = 0.056). Tumor associated macrophages (TAM) expression of PD-L1 increased after RT: 15.2% to 45.7% (p = 0.003). Samples from controls demonstrated no baseline (0%) or change in tumor PD-L1 expression. Freedom from DM was lower for patients with PD-L1 TAM expression post-RT (3 years: 49.7% vs. 87.8%, log-rank p = 0.006); TAM PD-L1 positivity remained an independent predictor for DM on multivariate analyses (Hazard ratio - 0.16, 95% confidence interval: 0.034-0.721, p = 0.042). PD-L1 expression on human STS tumor and TAM appears to elevate after pre-operative RT. Expression of PD-L1 on TAM after RT was associated with a higher rate of DM.

Author Info: (1) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (2) Deparment of Pathology, Emory University School of

Author Info: (1) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (2) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (3) Department of Therapeutic Radiology, Smilow Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (4) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (5) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (6) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (9) Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (10) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (11) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (12) Division of Orthopaedic Oncology, Department of Orthopedic Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (13) Division of Surgical Oncology, Department of Surgery, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. (14) Deparment of Pathology, Emory University School of Medicine, Atlanta, GA, USA. (15) Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.

Less

Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis

More

Purpose: Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design: We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis in vivo, BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. Results: The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity in vitro. Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-kappaB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. Conclusions: A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

Author Info: (1) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (2) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (3) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (4) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (5) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (6) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (7) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (8) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (9) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (10) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (11) Henan Key Laboratory for Esophageal Cancer Research, the First Affiliated Hospital, College of Zhengzhou University, Zhengzhou, China. (12) Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany. (13) Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, USA. (14) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. (15) Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. School of Life Sciences, Zhengzhou University, Zhengzhou, China. Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China.

Less

Vaccination-induced skin-resident memory CD8(+) T cells mediate strong protection against cutaneous melanoma

More

Memory CD8(+) T cell responses have the potential to mediate long-lasting protection against cancers. Resident memory CD8(+) T (Trm) cells stably reside in non-lymphoid tissues and mediate superior innate and adaptive immunity against pathogens. Emerging evidence indicates that Trm cells develop in human solid cancers and play a key role in controlling tumor growth. However, the specific contribution of Trm cells to anti-tumor immunity is incompletely understood. Moreover, clinically applicable vaccination strategies that efficiently establish Trm cell responses remain largely unexplored and are expected to strongly protect against tumors. Here we demonstrated that a single intradermal administration of gene- or protein-based vaccines efficiently induces specific Trm cell responses against models of tumor-specific and self-antigens, which accumulated in vaccinated and distant non-vaccinated skin. Vaccination-induced Trm cells were largely resistant to in vivo intravascular staining and antibody-dependent depletion. Intradermal, but not intraperitoneal vaccination, generated memory precursors expressing skin-homing molecules in circulation and Trm cells in skin. Interestingly, vaccination-induced Trm cell responses strongly suppressed the growth of B16F10 melanoma, independently of circulating memory CD8(+) T cells, and were able to infiltrate tumors. This work highlights the therapeutic potential of vaccination-induced Trm cell responses to achieve potent protection against skin malignancies.

Author Info: (1) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (2) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (3) Laboratory of

Author Info: (1) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (2) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (3) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (4) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (5) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (6) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (7) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (8) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. (9) Department of Microbiology and Immunology, Stanford University, CA, USA. (10) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile. Facultad de Ciencias Medicas, Escuela de Medicina, Universidad de Santiago de Chile, Santiago, Chile. (11) Centro de Investigacion Biomedica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile. (12) Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile. Millennium Institute on Immunology and Immunotherapy, Universidad de Chile, Santiago, Chile. (13) Department of Microbiology and Immunology, Stanford University, CA, USA. (14) Laboratory of Gene Immunotherapy, Fundacion Ciencia & Vida, Santiago, Chile.

Less

Immunosuppressive activity of tumor-infiltrating myeloid cells in patients with meningioma

More

Meningiomas WHO grade I and II are common intracranial tumors in adults that normally display a benign outcome, but are characterized by a great clinical heterogeneity and frequent recurrence of the disease. Although the presence of an immune cell infiltrate has been documented in these tumors, a clear phenotypical and functional characterization of the immune web is missing. Here, we performed an extensive immunophenotyping of peripheral blood and fresh tumor tissue at surgery by multiparametric flow cytometry in 34 meningioma patients, along with immunosuppressive activity of sorted cells of myeloid origin. Four subsets of myeloid cells, phenotypically corresponding to myeloid-derived suppressor cells (MDSCs) are detectable in the blood and in the tumor tissue of patients and three of them are significantly expanded in the blood of patients, but show no evidence of suppressive activity. At the tumor site, a large leukocyte infiltrate is present, predominantly constituted by CD33(+) myeloid cells, largely composed of macrophages endowed with suppressive activity and significantly expanded in grade II meningioma patients as compared to grade I.

Author Info: (1) IOV-IRCCS, Via Gattamelata, Padova, Italy. (2) Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. (3) IOV-IRCCS, Via Gattamelata, Padova, Italy. (4)

Author Info: (1) IOV-IRCCS, Via Gattamelata, Padova, Italy. (2) Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. (3) IOV-IRCCS, Via Gattamelata, Padova, Italy. (4) Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. (5) Department of Medicine, Verona University Hospital, Verona, Italy. (6) Department of Neurosurgery, Azienda Ospedaliera di Padova, Padova, Italy. (7) IOV-IRCCS, Via Gattamelata, Padova, Italy. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.

Less

Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy

More

Integration of hypofractionated body radiotherapy (H-RT) into immune checkpoint inhibitor (ICI) therapy may be a promising strategy to improve the outcomes of ICIs, although sufficient data is lacking regarding the safety and efficacy of this regimen. We, hereby, reviewed the safety and efficacy of this combination in 59 patients treated with H-RT during or within 8 weeks of ICI infusion and compared results with historical reports of ICI treatment alone. Most patients had RCC or melanoma. Median follow-up was 11 months. Most patients received either Nivolumab alone or with Ipilimumab; 83% received stereotactic RT and 17% received conformal H-RT. Any grade adverse events (AEs) were reported in 46 patients, and grade 3-4 in 12 patients without any treatment-related grade 5 toxicity. The most common grade 3 AEs were fatigue and pneumonitis. Grade 3-4 toxicities were higher with ICI combination and with simultaneous ICIs. Overall, most any-grade or grade >/=3 AE rates did not differ significantly from historically reported rates with single-agent or multi-agent ICIs. Toxicity did not correlate with H-RT site, dose, fraction number, tumor type, or ICI and H-RT sequencing. Median progression-free survival was 6.5 months. Objective response rate (ORR) was 26%; 10% had complete response (CR). Median duration of response was 9.4 +/- 4.6 months. H-RT of lung lesions was more likely to achieve CR than other sites. H-RT of bone lesions had a lower ORR than non-bone H-RT. In conclusion, combining body H-RT with ICIs is safe and promising. Prospective validation is warranted.

Author Info: (1) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (2) University of Texas Southwestern Medical Center, Department of Radiology, Dallas

Author Info: (1) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (2) University of Texas Southwestern Medical Center, Department of Radiology, Dallas, Texas, USA. (3) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (4) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (5) University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (6) University of Texas Southwestern Medical Center, Department of Internal Medicine, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (7) University of Texas Southwestern Medical Center, Department of Internal Medicine, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (8) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. (9) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (10) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (11) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (12) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (13) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (14) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (15) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. (16) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (17) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. (18) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (19) University of Texas Southwestern Medical Center, University of Texas Southwestern School of Medicine, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA. (20) University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, Texas, USA. University of Texas Southwestern Medical Center, Kidney Cancer Program, Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA.

Less

Differential Regulation of T-cell mediated anti-tumor memory and cross-protection against the same tumor in lungs versus skin

More

A major advantage of immunotherapy of cancer is that effector cells induced at one site should be able to kill metastatic cancer cells in other sites or tissues. However, different tissues have unique immune components, and very little is known about whether effector T cells induced against tumors in one tissue can work against the same tumors in other tissues. Here, we used CT26 murine tumor models to investigate anti-tumor immune responses in the skin and lungs and characterized cross-protection between the two tissues. Blockade of the function of Treg cells with anti-CD25 allowed for T cell-dependent rejection of s.c. tumors. When these mice were simultaneously inoculated i.v. with CT26, they also rejected tumors in the lung. Interestingly, in the absence of s.c. tumors, anti-CD25 treatment alone had no effect on lung tumor growth. These observations suggested that T cell-mediated anti-tumor protective immunity induced against s.c. tumors can also protect against lung metastases of the same tumors. In contrast, NKT cell-deficiency in CD1d(-/-) mice conferred significant protection against lung tumors but had no effect on the growth of tumors in the skin, and tumor rejection induced against the CT26 in the lung did not confer protection for the same tumor cells in the skin. Thus, effector cells against the same tumor do not work in all tissues, and the induction site of the effector T cells is critical to control metastasis. Further, the regulation of tumor immunity may be different for the same tumor in different anatomical locations.

Author Info: (1) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Michigan, USA. (2) Vaccine Branch

Author Info: (1) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor, Michigan, USA. (2) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. Institute for Public Health Genomics, Department of Genetics & Cell Biology, School for Oncology & Developmental Biology (GROW), FHML, Maastricht University, The Netherlands. (3) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. (4) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. (5) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. (6) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. (7) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA. (8) Vaccine Branch, CCR, NCI, NIH Bethesda, MD USA.

Less

Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response

More

The antitumor effect of metformin has been demonstrated in several types of cancer; however, the mechanisms involved are incompletely understood. In this study, we showed that metformin acts directly on melanoma cells as well as on the tumor microenvironment, particularly in the context of the immune response. In vitro, metformin induces a complex interplay between apoptosis and autophagy in melanoma cells. The anti-metastatic activity of metformin in vivo was assessed in several mouse models challenged with B16F10 cells. Metformin's activity was, in part, immune system-dependent, whereas its antitumor properties were abrogated in immunodeficient (NSG) mice. Metformin treatment increased the number of lung CD8-effector-memory T and CD4(+)Foxp3(+)IL-10(+) T cells in B16F10-transplanted mice. It also decreased the levels of Gr-1(+)CD11b(+) and RORgamma(+) IL17(+)CD4(+) cells in B16F10-injected mice and the anti-metastatic effect was impaired in RAG-1(-/-) mice challenged with B16F10 cells, suggesting an important role for T cells in the protection induced by metformin. Finally, metformin in combination with the clinical metabolic agents rapamycin and sitagliptin showed a higher antitumor effect. The metformin/sitagliptin combination was effective in a BRAFV600E/PTEN tamoxifen-inducible murine melanoma model. Taken together, these results suggest that metformin has a pronounced effect on melanoma cells, including the induction of a strong protective immune response in the tumor microenvironment, leading to tumor growth control, and the combination with other metabolic agents may increase this effect.

Author Info: (1) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. Department of Immunobiology, Yale

Author Info: (1) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA. (2) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (3) Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA. (4) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (5) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (6) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (7) Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo (EPM-UNIFESP), 04023-062 Sao Paulo, SP, Brazil. (8) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (9) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (10) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (11) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil. (12) Laboratory of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, 05508-900 Sao Paulo, SP, Brazil. (13) Department of Immunobiology, Yale University School of Medicine, 06520 New Haven, CT, USA. (14) Laboratory of Cancer Immunobiology, Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo (EPM-UNIFESP), 04023-062 Sao Paulo, SP, Brazil. (15) Laboratory of Transplantation Immunobiology, Department of Immunology, University of Sao Paulo, Institute of Biomedical Sciences, 05508-900 Sao Paulo, SP, Brazil.

Less

Association of T-Cell Receptor Repertoire Use With Response to Combined Trastuzumab-Lapatinib Treatment of HER2-Positive Breast Cancer: Secondary Analysis of the NeoALTTO Randomized Clinical Trial

More

Importance: Dual anti-HER2 blockade increased the rate of pathologic complete response (pCR) in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trial, and high immune gene expression was associated with pCR in all treatment arms. So far, no marker has been identified that is specifically associated with the benefit from dual HER2 blockade. Objective: To examine if use of the T-cell beta chain variable genes adds to the potential association of immune gene signatures with response to dual HER2 blockade. Design, Setting, and Participants: In the NeoALTTO trial, HER2-positive patients recruited between January 5, 2008, and May 27, 2010, were treated with paclitaxel plus either lapatinib or trastuzumab or both as neoadjuvant therapy. In this study, RNA sequencing data from baseline tumor specimens of 245 patients in the NeoALTTO trial were analyzed and reads were aligned to TRBV gene reference sequences using a previously published Basic Local Alignment Search Tool T-cell receptor mapping pipeline. Total TRBV gene use, Shannon entropy, and gene richness were calculated for each tumor, and nonnegative matrix factorization was used to define TRBV co-use metagenes (TMGs). The association between TRBV metrics, tumor genomic metrics, and response was assessed with multivariable logistic regression. Statistical analysis was performed from January 23 to December 2, 2017. Main Outcomes and Measures: The association between TRBV use metrics and pCR. Results: Among the 245 women with available data (mean [SD] age, 49 [11] years), total TRBV use correlated positively with a gene expression signature for immune activity (Spearman rho = 0.93; P < .001). High use of TRBV11-3 and TMG2, characterized by high use of TRBV4.3, TRBV6.3, and TRBV7.2, was associated with a higher rate of pCR to dual HER2-targeted therapy (TRBV11-3 interaction: odds ratio, 2.63 [95% CI, 1.22-6.47]; P = .02; TMG2 interaction: odds ratio, 3.39 [95% CI, 1.57-8.27]; P = .004). Immune-rich cancers with high TMG2 levels (n = 92) had significantly better response to dual HER2-targeted treatment compared with the single therapy arms (rate of pCR, 68% [95% CI, 52%-83%] vs 21% [95% CI, 10%-31%]; P < .001), whereas those with low TMG2 levels did not benefit from dual therapy. High TMG2 levels were also associated with a higher rate of pCR to the combined therapy in immune-poor tumors (n = 30; pCR, 50% [95% CI, 22%-78%] vs 6% [95% CI, 0%-16%]; P = .009). Conclusions and Relevance: Use patterns of TRBV genes potentially provide information about the association with response to dual HER2 blockade beyond immune gene signatures. High use of TRBV11.3 or TRBV4.3, TRBV6.3, and TRBV7.2 identifies patients who have a better response to dual HER2 targeted therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT00553358.

Author Info: (1) Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. Computational Biology and Bioinformatics Program, Yale University, New Haven, Connecticut. (2)

Author Info: (1) Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. Computational Biology and Bioinformatics Program, Yale University, New Haven, Connecticut. (2) Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. (3) Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. (4) Division of Cancer Medicine and Research, Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia. (5) Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. (6) Molecular Oncology Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain. (7) Department of Obstetrics and Gynecology, University of Munich, Munich, Germany. (8) Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. (9) Novartis AG, Basel, Switzerland. (10) Department of Oncology, Istituto Nazionale Tumori, Milan, Italy. (11) Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany. (12) Breast Medical Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. (13) Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. (14) Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York. Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medical College, New York, New York. (15) Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut. (16) Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

Less