Enhanced T-Cell Priming and Improved Anti-Tumor Immunity through Lymphatic Delivery of Checkpoint Blockade Immunotherapy.

An infusion of checkpoint blockade immunotherapy (CBI) has revolutionized cancer treatments for some patients, but the majority of patients experience disappointing responses. Because adaptive immune responses are mounted by the concentrated assembly of antigens, immune cells, and mediators in the secluded and protective environment of draining lymph nodes (dLNs), we hypothesize that lymphatic delivery of CBI (αCTLA-4 and αPD-1) to tumor dLNs (tdLNs) improves anti-tumor responses over intravenous (i.v.) administration, and that vaccination against tumor associated antigen (TAA) further enhances these responses. Mono- and combination CBI were administered i.v. or through image-guided intradermal (i.d.) injection to reach tdLNs in vaccinated and unvaccinated animals bearing either primary or orthotopically metastasizing B16F10 melanoma. Vaccination and boost against TAA, Melan-A, was accomplished with virus-like particles (VLP) directed to tdLNs followed by VLP boost after CBI administration. Lymphatic delivery of CBIs reduced primary tumor size and metastatic tumor burden, alleviated the pro-tumorigenic immune environment, and improved survival over systemic administration of CBIs. Animals receiving CBIs lymphatically exhibited significantly enhanced survival over those receiving therapies administered partially or completely through systemic routes. By combining vaccination and CBI for effective T-cell priming in the protected environment of dLNs, anti-tumor responses may be improved.

Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR.

ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.

A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy.

Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.

Frecuencia de anticuerpos contra el virus de la hepatitis E en donantes de sangre del municipio de Yarumal, Antioquia / Frequency of Antibodies to Hepatitis E In Blood Donors in the Municipality of Yarumal, Antioquia

Introducción: el virus de la Hepatitis E (VHE), transmitido por la ruta fecal-oral, causa enfermedad hepática aguda. En Colombia se han realizado algunos estudios en pacientes con diagnóstico de hepatitis viral, en trabajadores de fincas porcícolas, en población porcina y en muestras ambientales. Objetivo: evaluar la presencia de anticuerpos anti-VHE en muestras de donantes de sangre del municipio de Yarumal, departamento de Antioquia. Metodología: se obtuvieron muestras de suero de donantes de sangre colectadas por la Cruz Roja Colombiana en una campaña de donación voluntaria en el municipio de Yarumal. En las muestras se determinó la presencia de anticuerpos anti-VHE tipo IgM e IgG mediante estuche comercial de ELISA. Resultados: se analizaron 42 muestras de suero, 19 de las cuales (45,2%) fueron positivas para anticuerpos anti-VHE IgG. Ninguna de las muestras fue positiva para anticuerpos anti-VHE tipo IgM. Conclusiones: este es el primer reporte de anticuerpos anti-VHE en donantes de sangre en Colombia. La frecuencia de anti-VHE (45,2%) es mayor a lo reportado previamente en otros estudios realizados en el país y a lo reportado en donantes de sangre en otros países de América Latina. Esta frecuencia podría estar relacionada con el contacto con cerdos infectados, así como con la exposición a agua contaminada con el virus. Sin embargo, estudios adicionales deben ser realizados en otras poblaciones similares en el país para confirmar este hallazgo.

Introduction: The hepatitis E virus (HEV) is transmitted via the fecal-oral route and causes acute liver disease. In Colombia there have been some studies of patients who have been diagnosed with viral hepatitis, of swine farm workers and in environmental samples. Objective: The objective of this study was evaluate samples from blood donors in the municipality of Yarumal in the department of Antioquia for the presence of anti-HEV antibodies. Methods: Serum samples were obtained from blood donated to the Colombian Red Cross by blood donors on a voluntary basis in a campaign in the municipality of Yarumal. Samples in the presence of anti-HEV IgM and IgG ELISA using commercial kit was determined.Results: Forty-two serum samples were analyzed: 19 (45.2%) were positive for anti-HEV IgG. None of the samples were positive for anti-HEV IgM. Conclusions: This is the first report of anti-HEV antibodies in blood donors in Colombia. The frequency of anti-HEV (45.2%) is higher than previously reported in other studies in this country and in blood donors in other Latin American countries. This frequency may be linked to contact with infected pigs and to exposure to water contaminated with the virus. However, additional studies should be conducted in similar populations in the country to confirm this finding