Kerdidani, D. | bioRxiv Science

bioRxiv2022

Interferon-induced lysosomal membrane permeabilization causes cDC1-deserts in tumors.

T cell immunity requires antigen capture by conventional dendritic cells (cDCs), digestion and transfer to draining lymph nodes for presentation to antigen-inexperienced T cells. cDCs type I excel as cancer-antigen presenting cells, due to their ability to phagocytose, slowly digest apoptotic cancer cells and translocate cancer antigens to the cytosol for loading to MHCI and cross-presentation to CD8 T cells 1-3. In tumor tissues cDCs1 become particularly scarce and this restricts anti-tumour immunity, immunotherapy responses and patient survival 4-8. Tumor cDC1 paucity is not fully understood and no specific treatment currently exists. Here, we find that type I interferons (IFN) induce lysosomal stress, lysosomal membrane permeabilization (LMP) and lysosomal-dependent cell death (LDCD) in cDCs1. Two parallel pathways downstream of IFNAR1 converged to induce cDC1 LDCD. Up-regulation of expression of lysosomal genes enhanced the proteolytic activity of lysosomes, while IFN-inducible guanylate binding protein-2 (GBP-2) accumulated in the membrane of the stressed lysosomes, leading to LMP, proteolytic enzyme release and death. Protease inhibition or GBP-2 repression rescued cDCs1 from LDCD and boosted their anti-tumor efficacy. GBPs are amongst the most abundant IFN-induced genes and known to form toxic pores in pathogen-containing vacuoles and pathogen membranes 9. GBP-2-driven LMP is likely due to the ability of GBP-2 to form pores on the lysosomes of cDC1s. This might have evolved as a physiological mechanism of antigen translocation to the cytosol for cross-presentation 10. We anticipate our findings to be a starting point for more rational cDC1-directed immunotherapies. For instance, protease inhibition, GBP-2 downregulation or induced expression of LMP repair machinery may boost cDC1 efficacy in adoptive cell therapies or their use as live vaccines11-13.

immunology↗

bioRxiv2020

Antigen-presenting fibroblasts sustain anti-tumour CD4+ T cells in situ via MHCIIp-TCR and C1q-C1qbp binding.

A key unknown of the functional space in tumor immunity is whether physiologically relevant cancer antigen presentation occurs solely in draining lymph nodes versus tumors. Professional antigen presenting cells, i.e. the dendritic cells, are scarce and immature within tumors, greatly outnumbered by MHCII expressing non-hematopoietic cells, such as antigen-presenting cancer-associated fibroblasts (apCAFs). We hypothesized that after their exit from tumor-draining lymph nodes T cells depend on a second wave of antigen presentation provided in situ by structural cells. We show that dense apCAF regions in human lung tumors define hot immunological spots with increased numbers of CD4 T cells. The transcriptomic profile of human lung apCAFs aligned to that of pancreatic apCAFs across mice and humans and were both enriched for alveolar type II genes, suggesting an epithelial origin. Mechanistically, human apCAFs directly activated the TCRs of adjacent effector CD4 T cells and at the same time produced high levels of c1q, which acted on surface c1qbp on T cells to rescue them from apoptosis. Fibroblast-specific deletion of MHCII in mice impaired local MHCII immunity and accelerated tumor growth, while inducing c1qbp overexpression in adoptively transferred T cells expanded their numbers within tumors and reduced tumour burden. Collectively, our work shows that tumor T cell immunity post lymph node exit requires peripheral antigen presentation by a subset of CAFs and proposes a new conceptual framework upon which effective cancer immunotherapies can be built.

immunology↗