: Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined approaches. Here, we used spatial transcriptomics to investigate the multidimensional organization of TNBC at diagnosis and explore the contribution of each cell component to response to NAC. Starting from a consecutive retrospective series of TNBC cases, we designed a case-control study including 24 patients with TNBC of which 12 experienced a pathologic complete response (pCR) and 12 no-response or progression (pNR) after NAC. Over 200 regions of interest (ROI) were profiled. Our computational approaches described a model that recapitulates clinical response to therapy. The data were validated in an independent cohort of patients. Differences in the transcriptional program were detected in the tumor, stroma, and immune infiltrate comparing patients with a pCR with those with pNR. In pCR, spatial contamination between the tumor mass and the infiltrating lymphocytes was observed, sustained by a massive activation of IFN-signaling. Conversely, pNR lesions displayed increased pro-angiogenetic signaling and oxygen-based metabolism. Only modest differences were observed in the stroma, revealing a topology-based functional heterogeneity of the immune infiltrate. Thus, spatial transcriptomics provides fundamental information on the multidimensionality of TNBC and allows an effective prediction of tumor behavior. These results open new perspectives for the improvement and personalization of therapeutic approaches to TNBCs.

Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer / Donati, B.; Reggiani, F.; Torricelli, F.; Santandrea, G.; Rossi, T.; Bisagni, A.; Gasparini, E.; Neri, A.; Cortesi, L.; Ferrari, G.; Bisagni, G.; Ragazzi, M.; Ciarrocchi, A.. - In: CANCER IMMUNOLOGY RESEARCH. - ISSN 2326-6066. - 12:1(2024), pp. 120-134. [10.1158/2326-6066.CIR-23-0076]

Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Santandrea G.;Ragazzi M.;
2024

Abstract

: Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined approaches. Here, we used spatial transcriptomics to investigate the multidimensional organization of TNBC at diagnosis and explore the contribution of each cell component to response to NAC. Starting from a consecutive retrospective series of TNBC cases, we designed a case-control study including 24 patients with TNBC of which 12 experienced a pathologic complete response (pCR) and 12 no-response or progression (pNR) after NAC. Over 200 regions of interest (ROI) were profiled. Our computational approaches described a model that recapitulates clinical response to therapy. The data were validated in an independent cohort of patients. Differences in the transcriptional program were detected in the tumor, stroma, and immune infiltrate comparing patients with a pCR with those with pNR. In pCR, spatial contamination between the tumor mass and the infiltrating lymphocytes was observed, sustained by a massive activation of IFN-signaling. Conversely, pNR lesions displayed increased pro-angiogenetic signaling and oxygen-based metabolism. Only modest differences were observed in the stroma, revealing a topology-based functional heterogeneity of the immune infiltrate. Thus, spatial transcriptomics provides fundamental information on the multidimensionality of TNBC and allows an effective prediction of tumor behavior. These results open new perspectives for the improvement and personalization of therapeutic approaches to TNBCs.
2024
12
1
120
134
Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer / Donati, B.; Reggiani, F.; Torricelli, F.; Santandrea, G.; Rossi, T.; Bisagni, A.; Gasparini, E.; Neri, A.; Cortesi, L.; Ferrari, G.; Bisagni, G.; Ragazzi, M.; Ciarrocchi, A.. - In: CANCER IMMUNOLOGY RESEARCH. - ISSN 2326-6066. - 12:1(2024), pp. 120-134. [10.1158/2326-6066.CIR-23-0076]
Donati, B.; Reggiani, F.; Torricelli, F.; Santandrea, G.; Rossi, T.; Bisagni, A.; Gasparini, E.; Neri, A.; Cortesi, L.; Ferrari, G.; Bisagni, G.; Ragazzi, M.; Ciarrocchi, A.
File in questo prodotto:
File Dimensione Formato  
canc imm res 2024.pdf

Accesso riservato

Tipologia: Versione pubblicata dall'editore
Dimensione 10.95 MB
Formato Adobe PDF
10.95 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1334227
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? ND
social impact