Host tissue determinants of tumour immunity

Abstract

Although common evolutionary principles drive the growth of cancer cells regardless of the tissue of origin, the microenvironment in which tumours arise substantially differs across various organ sites. Recent studies have established that, in addition to cell-intrinsic effects, tumour growth regulation also depends on local cues driven by tissue environmental factors. In this Review, we discuss how tissue-specific determinants might influence tumour development and argue that unravelling the tissue-specific contribution to tumour immunity should help the development of precise immunotherapeutic strategies for patients with cancer.

Fig. 1 |. The cellular and architectural heterogeneity of the tumour microenvironment at distinct cancer sites.

Schematics of representative histological patterns of glioblastoma (part a), skin melanoma (part b), pancreatic ductal adenocarcinoma (part c), lung adenocarcinoma (part d) and clear-cell renal cell carcinoma (part e) are shown. Tumour lesions at distinct tissue sites display different tumour mass organization, stroma to tumour ratios and levels of fibrotic reaction. In addition to neoplastic cells, each tumour microenvironment contains cells derived from both circulating cells and local cells such as fibroblasts, pericytes and endothelial cells that may differentially impact antitumour immune responses across cancer sites. For each tumour type, a colour-coded heatmap (red: high; blue: low) shows the level of dominance of macrophage or lymphocyte infiltrate, presence of tertiary lymphoid structures (TLSs), matrix deposition and response to immune checkpoint blockade (ICB). CAF, cancer-associated fibroblast; ECM, extracellular matrix;Mac, macrophage; T, T cell.

Fig. 2 |. Cellular contributors to tissue-specific antitumour responses.

Blood vessels across anatomical sites can differentially control tumour immune infiltrate through distinct levels of expression of adhesion molecules, cohesiveness and pericyte coverage, regulating immune cell extravasation. While the differential impact of lymphatic vessels on the immune infiltrate across cancer types is poorly understood, it is now well established that lymphatics help shape immune responses by promoting tolerance to self-antigens, archiving antigen for later presentation and dampening effector immune responses^–. Cancer-associated fibroblasts modulate antitumour immune responses by secreting chemokines, cytokines, growth factors and reactive oxygen species, as well as producing and remodelling the stromal matrix that serves both a guiding and a barrier function for immune cells. Emerging evidence shows that commensal bacteria can set the tone of antitumour immune responses both systemically and locally, for example, by stimulating immune cells to secrete inflammatory cytokines. Tissue-resident cells, which include macrophages, dendritic cells and memory T cells, contribute to shaping antitumour immune responses by acting directly on tumour cells or modulating infiltrating immune cells. Nerve cells, whose presence has been reported in a limited number of cancer types, influence tumour cell survival, angiogenesis and the function of immune cells such as macrophages by releasing neurotransmitters and growth factors. CCL2, CC-chemokine 1igand2; CLEVER1, common lymphatic endothelial and vascular endothelial receptor 1; CSF1, colony-stimulating factor 1; ECM, extracellular matrix; ICAM, intercellular cell adhesion molecule; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; NO, nitric oxide; PG E2, prostaglandin E2.

Fig. 3 |. Therapeutic implications of tumour cell-intrinsic and tumour cell-extrinsic factors dependent on tissue specificity.

Each tumour component has characteristics leading to poor or favourable immune recognition and outcome. Presence of the pin symbol in the column for proposed therapeutics indicates already approved modalities. FLT3L, FMS-like tyrosine kinase 3 ligand; HLA, human leukocyte antigen; IFNγ, interferon-γ; NK, natural killer; NA, not available; TGFβ, transforming growth factor-β; T_H cell, T helper cell; TLS, tertiary lymphoid structure; T_reg cell, regulatory T cell.