Frontiers in immunology · 2026
Spatial organization of the tumor immune microenvironment in LAR+ triple-negative breast cancer.
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Lucchetti Donatella, Di Leone Alba, Sabbatinelli Giulia, Toma Federica, Antonio Franco, Cellini Beatrice, Colella Filomena, Pazzaglia Erica, Parrillo Chiara, Giacó Luciano, Santoro Angela, Piermattei Alessia, Colonna Rita, Franceschini Gianluca, Sgambato Alessandro
Аннотация
BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous disease lacking approved targeted therapies and standardized treatment regimens. Among its molecular subtypes, luminal androgen receptor-positive (LAR+) TNBC is characterized by reduced proliferative activity and a lower sensitivity to chemotherapy. The tumor immune microenvironment (TIME) plays a critical role in shaping treatment responses; however, its spatial organization and cellular composition in LAR+ TNBC remain poorly understood.
METHODS: In this exploratory study, we performed multiplex immunofluorescence analysis to characterize 18 immune and tumor cell subtypes in paired pre- and post-neoadjuvant therapy (NAT) samples from small, exploratory cohort of patients with LAR+ TNBC, stratified by pathological complete response (pCR). We assessed immune cell composition, expression of exhaustion markers, and spatial relationships among cellular populations to explore TIME features associated with different pathological responses.
RESULTS: Patients who achieved pCR displayed higher pre-treatment densities of specific immune subsets, including CD20+PD-1+, CD4+FOXP3+, and CD8+PD-1+TIM3+ cells, consistent with an immune-enriched microenvironment. Spatial analyses revealed distinct patterns between Responders (Resp) and Non-Responders (NoResp). In Resp, tumor cells (PANCK+) were initially located closer to PD-L1-expressing tumor cells (PANCK+PD-L1+), with this proximity decreasing after NAT. In contrast, in non-Resp, immunosuppressive tumor cells moved closer to tumor cells following treatment. Moreover, NAT in Resp was associated with a spatial repositioning of CD4+ and CD8+ T cells toward tumor cells. B cells and regulatory B cells (Bregs) also exhibited differential spatial dynamics between the two groups.
CONCLUSIONS: This exploratory analysis describes distinct immune compositions and spatial arrangements of the TIME in LAR+ TNBC. Our findings suggest that specific immune enrichments and spatial remodeling patterns may differ between patients with different pathological outcomes, whereas the persistence of immunosuppressive niches characterizes non-Resp. Given the small sample size and the inclusion of immune checkpoint inhibitors in a subset of patients, all of whom achieved pCR, these observations should be considered strictly hypothesis-generating. Larger and more homogeneous cohorts will be required to validate these findings and to determine their potential clinical relevance.
METHODS: In this exploratory study, we performed multiplex immunofluorescence analysis to characterize 18 immune and tumor cell subtypes in paired pre- and post-neoadjuvant therapy (NAT) samples from small, exploratory cohort of patients with LAR+ TNBC, stratified by pathological complete response (pCR). We assessed immune cell composition, expression of exhaustion markers, and spatial relationships among cellular populations to explore TIME features associated with different pathological responses.
RESULTS: Patients who achieved pCR displayed higher pre-treatment densities of specific immune subsets, including CD20+PD-1+, CD4+FOXP3+, and CD8+PD-1+TIM3+ cells, consistent with an immune-enriched microenvironment. Spatial analyses revealed distinct patterns between Responders (Resp) and Non-Responders (NoResp). In Resp, tumor cells (PANCK+) were initially located closer to PD-L1-expressing tumor cells (PANCK+PD-L1+), with this proximity decreasing after NAT. In contrast, in non-Resp, immunosuppressive tumor cells moved closer to tumor cells following treatment. Moreover, NAT in Resp was associated with a spatial repositioning of CD4+ and CD8+ T cells toward tumor cells. B cells and regulatory B cells (Bregs) also exhibited differential spatial dynamics between the two groups.
CONCLUSIONS: This exploratory analysis describes distinct immune compositions and spatial arrangements of the TIME in LAR+ TNBC. Our findings suggest that specific immune enrichments and spatial remodeling patterns may differ between patients with different pathological outcomes, whereas the persistence of immunosuppressive niches characterizes non-Resp. Given the small sample size and the inclusion of immune checkpoint inhibitors in a subset of patients, all of whom achieved pCR, these observations should be considered strictly hypothesis-generating. Larger and more homogeneous cohorts will be required to validate these findings and to determine their potential clinical relevance.