Aramburu, J. | Search bioRxiv

bioRxiv2025

Site-specific immunogenicity and anti-PD1 response in mismatch repair deficient lung adenocarcinoma models

Immunotherapy has revolutionized cancer treatment, yet responses vary significantly based on tumour characteristics and microenvironment. Here, we developed and analysed subcutaneous and orthotopic immunocompetent mice models of mismatch repair-deficient (dMMR) lung adenocarcinoma (LUAD) by selectively ablating Mlh1. Subcutaneous tumours demonstrated partial sensitivity to anti-PD1 therapy, characterized by tumour volume reduction without significant changes in immune infiltration. In contrast, orthotopic tumours exhibited robust responses, with substantial reductions in tumour burden, enhanced immune infiltration, and increased CD4+ memory T cells, highlighting the critical role of anatomical site and tumour microenvironment in shaping immunotherapy outcomes. Our findings emphasise the relevance of orthotopic models for preclinical evaluation and suggest that they more accurately reflect clinical responses to immune checkpoint blockade in dMMR LUAD.

cancer biology↗

bioRxiv2024

Effector T cells in poorly perfused tumor regions exhibit a distinct signature of augmented IFN response and reduced PD-1 expression

Effector T lymphocytes are avid glucose consumers, but can function in the nutrient-poor environments of tumors. However, availability of blood-delivered nutrients throughout the tumor is not homogeneous, and how this affects effector T cells is not well known. Here we have isolated tumor-infiltrating T lymphocytes (TILs) from mouse solid tumors by their capacity to capture blood-transported probes, and compared them with glucose-restricted T cells. Glucose restriction in vitro arrested cell proliferation but reduced only moderately the induction of hallmark glucose-dependent cytokines interferon gamma (IFN{gamma}) and IL-17. In vivo, effector TILs with reduced access to blood had characteristics of glucose-restricted cells, such as reduced expression of IFN{gamma} and genes associated with cell proliferation. However, they expressed more CXCR3, which identifies effective antitumor T lymphocytes, showed an enhanced IFN response signature, and had reduced expression of surface PD-1. We also identified genes regulated by the enzyme ACSS2, which allows TILs to sustain gene expression in glucose-poor environments. Thus, effector T lymphocytes infiltrating tumors express different gene signatures in regions with different accessibility to blood, and can maintain specific glucose-dependent responses even in poorly perfused tumor regions. Our results can help better understand nutrient-dependent TIL heterogeneity in changing tumor microenvironments. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/601540v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@115d6beorg.highwire.dtl.DTLVardef@c56904org.highwire.dtl.DTLVardef@71b324org.highwire.dtl.DTLVardef@a804d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗