Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

Loi, Sherene; Salgado, Roberto; Adams, Sylvia; Pruneri, Giancarlo; Francis, Prudence A.; Lacroix-Triki, Magali; Joensuu, Heikki; Dieci, Maria Vittoria; Badve, Sunil; Demaria, Sandra; Gray, Robert J.; Munzone, Elisabetta; Drubay, Damien; Lemonnier, Jérôme; Sotiriou, Christos; Kellokumpu‐Lehtinen, Pirkko; Vingiani, Andrea; Gray, Kathryn P.; Varga, Andrea; Denkert, Carsten; Piccart, Martine; Roblin, Elvire; Michiels, Stefan

doi:10.1038/s41523-021-00362-1

Cited by 52 publications

(44 citation statements)

References 12 publications

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“…7B), supporting the involvement of the MUC1-C®PBRM1 pathway in conferring DNA damage resistance. An important factor in the responsiveness of TNBCs to chemotherapy is the presence of TILs (58,59). In this respect, patients with TNBCs harboring high TILs in the TME experience significant improvement in disease-free survival (DFS) in response to chemotherapy compared to those with low TILs (58,59).…”

Section: Involvement Of Muc1-c In Conferring Dna Damage Resistance Andmentioning

confidence: 99%

MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

Yamashita

Morimoto

Fushimi

et al. 2022

Molecular Cancer Research

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The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 and IRF1 are essential effectors of type I and II interferon (IFN) pathways. Here, we report that MUC1-C is necessary for PBRM1 expression and that it forms a nuclear complex with PBRM1 in TNBC cells. Analysis of global transcriptional (RNA-seq) and chromatin accessibility (ATAC-seq) profiles further demonstrated that MUC1-C and PBRM1 drive STAT1 and IRF1 expression by increasing chromatin accessibility of promoter-like signatures (PLSs) on their respective genes. We also found that MUC1-C, PBRM1, and IRF1 increase the expression and chromatin accessibility on PLSs of the (i) type II IFN pathway IDO1 and WARS genes and (ii) type I IFN pathway RIG-I, MDA5, and ISG15 genes that collectively contribute to DNA damage resistance and immune evasion. In support of these results, targeting MUC1-C in wild-type BRCA TNBC cells enhanced carboplatin-induced DNA damage and the loss of self-renewal capacity. In addition, MUC1-C was necessary for DNA damage resistance, self-renewal, and tumorigenicity in olaparib-resistant BRCA1-mutant TNBC cells. Analysis of TNBC tumors corroborated that (i) MUC1 and PBRM1 are associated with decreased responsiveness to chemotherapy and (ii) MUC1-C expression is associated with the depletion of tumor-infiltrating lymphocytes (TILs). These findings demonstrate that MUC1-C activates PBRM1, and thereby chromatin remodeling of IFN-stimulated genes that promote chronic inflammation, DNA damage resistance, and immune evasion. Implications: MUC1-C is necessary for PBRM1-driven chromatin remodeling in chronic activation of IFN pathway genes that promote DNA damage resistance and immunosuppression.

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Section: Involvement Of Muc1-c In Conferring Dna Damage Resistance Andmentioning

confidence: 99%

MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

Yamashita

Morimoto

Fushimi

et al. 2022

Molecular Cancer Research

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“…Therefore, TILs in DCIS may also be conductive to the guidance of the additional adjuvant therapies and follow-up. Though TILs have been described as reliable, reproducible and inexpensive markers in breast cancer, and could up−/ down-stage traditional pathological-staging in early-stage TNBC [ 21 ], limited research was focused on the utility of TILs in DCIS. On account of the convenience of TILs’ assessment, patients in clinical trials like ECOG-E5194 [ 22 , 23 ] can be used to re-analyze the association between TILs and ipsilateral breast events.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of tumor-infiltrating lymphocytes in DCIS: a meta-analysis

Mao

et al. 2022

BMC Cancer

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Background Tumor infiltrating lymphocytes (TILs) have been shown to be associated with the prognosis of breast ductal carcinoma in situ (DCIS). In this systematic review and meta-analysis, we investigated the role of TILs and TIL subsets in predicting the recurrence risk of DCIS. Method PubMed, Medline, Web of Science, Embase and Cochrane were searched to identify publications investigating the prognostic role of TILs in DCIS. After study screening, data extraction and risk of bias assessment, a meta-analysis was performed to assess the association between TILs (total TILs, CD4+, CD8+, FOXP3+, PD-L1+ TILs) and the risk of DCIS recurrence. Results A pooled analysis indicated that dense stromal TILs in DCIS were associated with a higher recurrence risk (HR 2.11 (95% CI 1.35–3.28)). Subgroup analysis showed that touching TILs (HR 4.73 (95% CI 2.28–9.80)) was more precise than the TIL ratio (HR 1.49 (95% CI 1.11–1.99)) in estimating DCIS recurrence risk. Moreover, the prognostic value of TILs seemed more suitable for patients who are diagnosed with DCIS and then undergo surgery (HR 2.77, (95% CI 1.26–6.07)) or surgery accompanied by radiotherapy (HR 2.26, (95% CI 1.29–3.95)), than for patients who receive comprehensive adjuvant therapies (HR 1.16, (95% CI 1.35–3.28)). Among subsets of TILs, dense stromal PD-L1+ TILs were valuable in predicting higher recurrence risk of DCIS. Conclusion This systematic review and meta-analysis suggested a non-favorable prognosis of TILs and stromal PD-L1+ TILs in DCIS and indicated an appropriate assessment method for TILs and an eligible population.

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“…To compare TME functions between the two AITL groups, TIL subset proportion, TRB and IGH repertoires, and gene expression profiles were examined. TIL subsets and proportions directly reflected TME immune function and have been shown to be predictive of various malignancies ( 17 – 19 ). TR and IGH repertoires of TME dictate TIL-T and TIL-B variety and represent the ability to identify tumor antigens and combat tumor immunoevasion ( 13 , 14 ).…”

Section: Discussionmentioning

confidence: 99%

Angioimmunoblastic T-cell lymphoma with predominant CD8+ tumor-infiltrating T-cells is a distinct immune pattern with an immunosuppressive microenvironment

et al. 2022

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BackgroundAngioimmunoblastic T-cell lymphoma (AITL) has a rich tumor microenvironment (TME) that typically harbors plenty of CD4+tumor infiltrating lymphocytes, (TIL)-T-cells (so called common AITL). Nonetheless, AITL with large numbers of CD8+TIL-Ts that outnumber CD4+cells have been observed (CD8-predominant AITL). However, detailed comparison of CD8-predominant AITL and common AITL are still lacking.MethodsWe compared clinicopathological features, TIL subsets, TME T cell receptor-β (TRB), and immunoglobulin heavy chain (IGH) repertoires, and gene expression profiles in six CD8-predominant and 12 common AITLs using case-control matching (2014 to 2019).ResultsComparing with common AITLs, CD8-predominant AITLs showed more frequent edema (P = 0.011), effusion (P = 0.026), high elevated plasma EBV-DNA (P = 0.008), and shorter survival (P = 0.034). Moreover, they had more pronounced eosinophil increase (P = 0.004) and a higher Ki67 index (P = 0.041). Flow cytometry revealed an inverted CD4/CD8 ratio in TIL-Ts and lower TIL-B proportions (P = 0.041). TRB repertoire metrics deteriorated, including lower productive clones (P = 0.014) and higher clonality score (P = 0.019). The IGH repertoire was also narrowed, showing a higher proportion of the top 10 clones (P = 0.002) and lower entropy (P = 0.027). Gene expression analysis showed significant enrichment for upregulated negative regulation of immune system processes and downregulated T-cell activation and immune cell differentiation.ConclusionOur findings demonstrated that CD8-predominant AITL is a distinct immune pattern of AITL characterized by anti-tumor immunity impairment and an immunosuppressive microenvironment. These characteristics can interpret its severe clinical manifestations and poor outcomes.

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Tumor infiltrating lymphocyte stratification of prognostic staging of early-stage triple negative breast cancer

Cited by 52 publications

References 12 publications

MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

MUC1-C Dictates PBRM1-Mediated Chronic Induction of Interferon Signaling, DNA Damage Resistance, and Immunosuppression in Triple-Negative Breast Cancer

Prognostic value of tumor-infiltrating lymphocytes in DCIS: a meta-analysis

Angioimmunoblastic T-cell lymphoma with predominant CD8+ tumor-infiltrating T-cells is a distinct immune pattern with an immunosuppressive microenvironment

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