A Pathologically Friendly Strategy for Determining the Organ‐specific Spatial Tumor Microenvironment Topology in Lung Adenocarcinoma Through the Integration of snRandom‐seq and Imaging Mass Cytometry

Abstract

Heterogeneous organ‐specific responses to immunotherapy exist in lung cancer. Dissecting tumor microenvironment (TME) can provide new insights into the mechanisms of divergent responses, the process of which remains poor, partly due to the challenges associated with single‐cell profiling using formalin‐fixed paraffin‐embedded (FFPE) materials. In this study, single‐cell nuclei RNA sequencing and imaging mass cytometry (IMC) are used to dissect organ‐specific cellular and spatial TME based on FFPE samples from paired primary lung adenocarcinoma (LUAD) and metastases. Single‐cell analyses of 84 294 cells from sequencing and 250 600 cells from IMC reveal divergent organ‐specific immune niches. For sites of LUAD responding well to immunotherapy, including primary LUAD and adrenal gland metastases, a significant enrichment of B, plasma, and T cells is detected. Spatially resolved maps reveal cellular neighborhoods recapitulating functional units of the tumor ecosystem and the spatial proximity of B and CD4+ T cells at immunogenic sites. Various organ‐specific densities of tertiary lymphoid structures are observed. Immunosuppressive sites, including brain and liver metastases, are deposited with collagen I, and T cells at these sites highly express TIM‐3. This study originally deciphers the single‐cell landscape of the organ‐specific TME at both cellular and spatial levels for LUAD, indicating the necessity for organ‐specific treatment approaches.

Lymphocyte homing and recirculation with tumor tertiary lymphoid structure formation: predictions for successful cancer immunotherapy

“…The presence of CD38 + CD138 + plasma cells surrounding the B cell follicle is highly suggestive of the production of antibodies in situ ( 72 ). For lung cancer patients responding well to ICB therapy, significant enrichment sites of B cells, plasma cells and T cells were detected in a single-cell profiling study ( 73 ). One of the main effector functions associated with B cells in TLSs is the production of antigen-specific antibodies that can mark tumor cells for complement-mediated cell lysis, or antibody-dependent cellular cytotoxicity.…”