Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials

Marinelli, Daniele; Mazzotta, Marco; Pizzuti, Laura; Krasniqi, Eriseld; Gamucci, Teresa; Natoli, Clara; Grassadonia, Antonino; Tinari, Nicola; Tomao, Silverio; Sperduti, Isabella; Sanguineti, Giuseppe; Botticelli, Andrea; Fabbri, Agnese; Botti, Claudio; Ciliberto, Gennaro; Barba, Maddalena; Vici, Patrizia

doi:10.3390/cancers12092497

Cited by 17 publications

(10 citation statements)

References 66 publications

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“…Expression of ICRs on TILs has been associated with a better response to immunotherapies including immune checkpoint inhibitors (ICIs) as shown in advanced metastatic breast cancer by using combined modalities with chemotherapy [ 25 ]. Based on these encouraging results, recent studies focused on intensive investigations in neoadjuvant setting in combinations of ICIs with chemotherapeutic agents including anthracyclines, taxanes and platinum [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

et al. 2021

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Background The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs. Results The median age was 49 (24–76) years. The majority of patients were clinically T3–4 (n = 31, 50.8%) and clinically N1–3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9–70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066–0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12–0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07–0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17–0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15–0.78, p = 0.01) were found to be associated with improved survival. Conclusions These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

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Section: Introductionmentioning

confidence: 99%

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

et al. 2021

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“…Although immune-checkpoint disruption has transformed patient benefit in a number of cancer settings (Marinelli et al, 2020), further advances are needed to achieve wider effectiveness. To investigate whether IRE1α inhibition would complement immune-checkpoint blockade, we turned to the orthotopic EMT6 TNBC model, previously found to exhibit partial responsiveness to anti-programmed death ligand (PD-L)1 antibody therapy upon implantation in the mouse mammary fat pad (Mariathasan et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells

Guttman¹,

Thomas²,

Marsters³

et al. 2021

Preprint

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Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER) and upload onto major histocompatibility type I (MHC-I) protein complexes for cell-surface transport and cross-presentation. Perplexingly, DCs often exhibit activation of the ER-stress sensor IRE1α in the absence of classical ER stress—leaving the underlying mechanism unexplained. Here we show that antigen-derived hydrophobic peptides directly engage ER-resident IRE1α by masquerading as unfolded proteins. Furthermore, IRE1α activation depletes MHC-I heavy-chain mRNAs through regulated IRE1α-dependent decay (RIDD), thereby curtailing antigen cross-presentation. In tumor-bearing mice, IRE1α disruption increased MHC-I expression on tumor-infiltrating DCs, and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1α inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings elucidate the mechanism and consequence of antigen-driven IRE1α activation in DCs, yielding a promising combination strategy for cancer immunotherapy.

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“…There are ongoing investigations on different combinations of immunotherapy and chemotherapy, particularly in the neoadjuvant setting in triple-negative breast cancers [ 46 ]. Encouraging results obtained from these trials support the value of chemotherapy in augmenting the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Neither Tumor-Infiltrating Lymphocytes nor Cytotoxic T Cells Predict Enhanced Benefit from Chemotherapy in the DBCG77B Phase III Clinical Trial

Shenasa

Stovgaard

Jensen

et al. 2022

Cancers

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Recent studies have shown that immune infiltrates in the tumor microenvironment play a role in response to therapy, with some suggesting that patients with immunogenic tumors may receive increased benefit from chemotherapies. We evaluated this hypothesis in early breast cancer by testing the interaction between immune biomarkers and chemotherapy using materials from DBCG77B, a phase III clinical trial where high-risk premenopausal women were randomized to receive chemotherapy or no chemotherapy. Tissue microarrays were evaluated for tumor-infiltrating lymphocytes (TILs) assessed morphologically on hematoxylin and eosin-stained slides, and by immunohistochemistry for CD8, FOXP3, LAG-3, PD-1 and PD-L1. Following REMARK reporting guidelines, data analyses were performed according to a prespecified statistical plan, using 10-year invasive disease-free survival as the endpoint. Differences in survival probabilities between biomarker groups were evaluated by Kaplan–Meier and Cox proportional hazard ratio analyses and prediction for treatment benefit by an interaction test. Our results showed that stromal TILs were associated with an improved prognosis (HR = 0.93; p-value = 0.03), consistent with previous studies. However, none of the immune biomarkers predicted benefit from chemotherapy in the full study set nor within major breast cancer subtypes. Our study indicates that primary tumors with higher immune infiltration do not derive extra benefit from cyclophosphamide-based cytotoxic chemotherapy.

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Neoadjuvant Immune-Checkpoint Blockade in Triple-Negative Breast Cancer: Current Evidence and Literature-Based Meta-Analysis of Randomized Trials

Cited by 17 publications

References 66 publications

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells

Neither Tumor-Infiltrating Lymphocytes nor Cytotoxic T Cells Predict Enhanced Benefit from Chemotherapy in the DBCG77B Phase III Clinical Trial

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