Dissecting the tumor microenvironment in response to immune checkpoint inhibitors via single-cell and spatial transcriptomics

Abstract

Cancer is a disease that undergoes selective pressure to evolve during its progression, becoming increasingly heterogeneous. Tumoral heterogeneity can dictate therapeutic response. Transcriptomics can be used to uncover complexities in cancer and reveal phenotypic heterogeneity that affects disease response. This is especially pertinent in the immune microenvironment, which contains diverse populations of immune cells, and whose dynamic properties influence disease response. The recent development of immunotherapies has revolutionized cancer therapy, with response rates of up to 50% within certain cancers. However, despite advances in immune checkpoint blockade specifically, there remains a significant population of non-responders to these treatments. Transcriptomics can be used to profile immune and other cell populations following immune-checkpoint inhibitor (ICI) treatment, generate predictive biomarkers of resistance or response, assess immune effector function, and identify potential immune checkpoints. Single-cell RNA sequencing has offered insight into mRNA expression within the complex and heterogeneous tumor microenvironment at single-cell resolution. Spatial transcriptomics has enabled measurement of mRNA expression while adding locational context. Here, we review single-cell sequencing and spatial transcriptomic research investigating ICI response within a variety of cancer microenvironments.

Keywords: Immunotherapy; Single-cell; Transcriptomics; Tumor microenvironment.

Fig. 1

Cellular signaling and interaction in the tumor microenvironment (TME) in response to immune checkpoint inhibitors (ICIs). Adaptive and innate immune cell signaling within the TME of responders and non-responders to ICIs. Left: Increased CD44 expression promotes acquisition of cancer stem cell features and metastasis, alongside SPP1, CCL5, CD163, and ITGAM + macrophages. Reduced checkpoint expression on T cell surfaces and increased immunosuppressive molecule expression promotes refractory response to ICIs. Right: Decreased immunosuppressive cell abundance and secretion of anti-tumor effector molecules, coupled with increased checkpoint expression, renders tumors more responsive to ICIs. CAF, cancer-associated fibroblast; DC, dendritic cell; Treg, regulatory T-cell. (Created with BioRender.com)

Fig. 2

Spatial distribution and interactions of cells within the TME of ICI responders vs. non-responders. Left: High CD163 + intratumoral infiltration is associated with worse clinical outcomes in NSCLC [61]. A tumor immune “barrier” (TIB) structure in the HCC microenvironment leads to resistance to ICIs [68]. SPP1 + macrophages and CAFs interact to promote the formation of the TIB structure and limit immune infiltration of tumors. Right: Mature TLS in RCC patients responding to ICI mediates maturation of B cells, and allows for selection, clonal amplification and dissemination of IgG-producing PCs [65]. TME, tumor microenvironment; ICI, immune-checkpoint inhibitor; NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; CAF, cancer-associated fibroblasts; NSCLC, non-small cell lung cancer; TAM, tumor-associated macrophages; TLS, tertiary lymphoid structure; RCC, renal cell cancer; PC, plasma cell. (Created with BioRender.com)