Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities

Abstract The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types 1,2 . Intratumoral host–microbiota studies have so far largely relied on bulk tissue analysis 1–3 , which obscures the spatial distribution and localized effect of the microbiota within tumours. Here, by applying in situ spatial-profiling technologies 4 and single-cell RNA sequencing 5 to oral squamous cell carcinoma and colorectal cancer, we reveal spatial, cellular and molecular host–microbe interactions. We adapted 10x Visium spatial transcriptomics to determine the identity and in situ location of intratumoral microbial communities within patient tissues. Using GeoMx digital spatial profiling 6 , we show that bacterial communities populate microniches that are less vascularized, highly immuno‑suppressive and associated with malignant cells with lower levels of Ki-67 as compared to bacteria-negative tumour regions. We developed a single-cell RNA-sequencing method that we name INVADEseq (invasion–adhesion-directed expression sequencing) and, by applying this to patient tumours, identify cell-associated bacteria and the host cells with which they interact, as well as uncovering alterations in transcriptional pathways that are involved in inflammation, metastasis, cell dormancy and DNA repair. Through functional studies, we show that cancer cells that are infected with bacteria invade their surrounding environment as single cells and recruit myeloid cells to bacterial regions. Collectively, our data reveal that the distribution of the microbiota within a tumour is not random; instead, it is highly organized in microniches with immune and epithelial cell functions that promote cancer progression. 

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Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer

Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.

/pdf/an-epigenetic-role-of-mitochondria-in-cancer-kumzb0ps.pdf

An Epigenetic Role of Mitochondria in Cancer

https://doi.org/10.1016/j.ccell.2022.10.008

High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

Lung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment. To map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyze 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and present the large scale, single cell resolution profiles of advanced NSCLCs. In addition to cell types described in previous single cell studies of early stage lung cancer, we are able to identify rare cell types in tumors such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also reveals a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC. Comprehensive profiles of tumour and microenvironment are critical to understand heterogeneity in non-small cell lung cancer (NSCLC). Here, the authors profile 42 late-stage NSCLC patients with single-cell RNA-seq, revealing immune landscapes that are associated with cancer subtype or heterogeneity.

/pdf/single-cell-profiling-of-tumor-heterogeneity-and-the-3rtywabsdv.pdf

Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer

Background Bone metastasis (BoM) is common in patients with advanced non-small cell lung cancer (NSCLC) and considered as one of the negative prognostic factors. However, the impact of BoM on clinical outcomes of patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear. Methods A total of 103 patients treated with ICI monotherapy and 101 patients treated with ICIs combined with chemotherapy or antiangiogenesis therapy were retrospectively analyzed. The differences in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) between BoM+ and BoM- were investigated. Results Of those 101 patients who received combination therapy, no significant difference between BoM- and BoM+ in terms of both median PFS and median OS (median PFS, 10.1 vs. 12.1 months, P = 0.6; median OS, NR vs. 24.6 months, P = 0.713) was determined. In contrast, of the 103 patients who received ICI monotherapy, BoM+ patients had an inferior PFS (4.2 vs. 6.7 months, P = 0.0484) and OS (12.5 vs. 23.9 months, P = 0.0036) compared with BoM- patients. The univariate and multivariate analysis in the ICI monotherapy group also identified BoM as an independent factor attenuating the efficacy of ICI monotherapy. Of all BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS (palliative radiotherapy: 12.5 vs. 16.7 months, P = 0.487; bisphosphonate drugs: 12.5 vs. 9.7 months, P = 0.568). Conclusions BoM attenuated the efficacy of ICI monotherapy in patients with advanced NSCLC. Of BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS. Other therapeutic strategies are needed for patients with BoM.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1759-7714.13597

Shanhao Chen

Papers

Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer

Adverse impact of bone metastases on clinical outcomes of patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

Mechanisms of Progression and Heterogeneity in Multiple Nodules of Lung Adenocarcinoma