Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.

Differences in Immunological Evasion of the Delta (B.1.617.2) and Omicron (B.1.1.529) SARS-CoV-2 Variants: A Retrospective Study on the Veneto Region's Population.

In December 2021-January 2022 the Veneto region in Italy faced an unprecedented wave of SARS-CoV-2 infections, even though both the vaccine coverage and the number of previously infected individuals keep increasing. In this study we address the protection against the SARS-CoV-2 infection offered by natural immunity and a three-dose regimen through a retrospective study based on Veneto's regional databases. In particular, we compared these protection levels during two distinct periods respectively representative of the Delta (B.1.617.2) and the Omicron (B.1.1.529) variants, in order to investigate and quantify the immunological evasion, especially of the Omicron. For each period we compared the incidence rate of infection among the population with various immunological protections against SARS-CoV-2 and performed a multivariable proportional hazard Cox binomial regression to assess the effectiveness afforded by both forms of active immunization. We found out that a previous SARS-CoV-2 infection (irrespective of its timing) offers 85% (83-87%) and 36% (33-39%) protection against being reinfected by Delta and Omicron, respectively. In addition, we estimated the third dose to be more effective in both periods and to have a minor proportional loss of effectiveness due to the rise of the Omicron variant, with an afforded effectiveness against SARS-CoV-2 Delta and Omicron infection of 97% (96-97%) and 47% (45-48%), respectively. Our findings suggest that viral variant factors may affect any form of active immunization but that receiving a booster vaccination cycle is more effective and less variable than natural immunity in terms of afforded protection against SARS-CoV-2 infections.