A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Immune-mediated inflammatory diseases (IMIDs) are a group of autoimmune and chronic inflammatory disorders with constantly increasing prevalence in the modern world. The vast majority of IMIDs develop as a consequence of complex mechanisms dependent on genetic, epigenetic, molecular, cellular, and environmental elements, that lead to defects in immune regulatory guardians of tolerance, such as dendritic (DCs) and regulatory T (Tregs) cells. As a result of this dysfunction, immune tolerance collapses and pathogenesis emerges. Deeper understanding of such disease driving mechanisms remains a major challenge for the prevention of inflammatory disorders. The recent renaissance in high throughput technologies has enabled the increase in the amount of data collected through multiple omics layers, while additionally narrowing the resolution down to the single cell level. In light of the aforementioned, this review focuses on DCs and Tregs and discusses how multi-omics approaches can be harnessed to create robust cell-based IMID biomarkers in hope of leading to more efficient and patient-tailored therapeutic interventions.

Emphysema assessment for personalized immunotherapy response prediction in lung cancer patients