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The article discusses a study which examined the differential patterns of gene expression in true interval breast cancer, which is defined as a cancer that truly appears following negative screening mammography. Topics discussed include the differential gene and protein expression profile in true interval and screen-detected cancers, microarray analysis, and the upregulation of the mammalian target of rapamycin (mTOR) signaling in true interval cancers.

Crosstalk between tumor and stromal cells in the tumor microenvironment alter its properties in ways that facilitate the invasive behavior of tumor cells. Here, we demonstrate that cancer-associated fibroblasts (CAF) increase the stiffness of the extracellular matrix (ECM) and promote anisotropic fiber orientation, two mechanical signals generated through a Snail1/RhoA/αSMA-dependent mechanism that sustains oriented tumor cell migration and invasiveness. Snail1-depleted CAF failed to acquire myofibroblastic traits in response to TGFβ, including RhoA activation, αSMA-positive stress fibers, increased fibronectin fibrillogenesis, and production of a stiff ECM with oriented fibers. Snail1 expression in human tumor-derived CAF was associated with an ability to organize the ECM. In coculture, a relatively smaller number of Snail1-expressing CAF were capable of imposing an anisotropic ECM architecture, compared with nonactivated fibroblasts. Pathologically, human breast cancers with Snail1+ CAF tended to exhibit desmoplastic areas with anisotropic fibers, lymph node involvement, and poorer outcomes. Snail1 involvement in driving an ordered ECM was further confirmed in wound-healing experiments in mice, with Snail1 depletion preventing the anisotropic organization of granulation tissue and delaying wound healing. Overall, our results showed that inhibiting Snail1 function in CAF could prevent tumor-driven ECM reorganization and cancer invasion. [ABSTRACT FROM AUTHOR]

In patients with trastuzumab-resistant HER2-positive breast cancer, the combination of everolimus (mTORC1 inhibitor) with trastuzumab failed to show a clinically significant benefit. However, the combination of mTOR inhibition and the antibody-drug conjugate (ADC) trastuzumab-emtansine (T-DM1) remains unexplored. We tested T-DM1 plus everolimus in a broad panel of HER2-positive breast cancer cell lines. The combination was superior to T-DM1 alone in four cell lines (HCC1954, SKBR3, EFM192A, and MDA-MB-36) and in two cultures from primary tumor cells derived from HER2-positive patient-derived xenografts (PDX), but not in BT474 cells. In the trastuzumab-resistant HCC1954 cell line, we characterized the effects of the combination using TAK-228 (mTORC1 and -2 inhibitor) and knockdown of the different mTOR complex components. T-DM1 did not affect mTOR downstream signaling nor induct autophagy. Importantly, mTOR inhibition increased intracellular T-DM1 levels, leading to increased lysosomal accumulation of the compound. The increased efficacy of mTOR inhibition plus T-DM1 was abrogated by lysosome inhibitors (chloroquine and bafilomycin A1). Our experiments suggest that BT474 are less sensitive to T-DM1 due to lack of optimal lysosomal processing and intrinsic resistance to the DM1 moiety. Finally, we performed several in vivo experiments that corroborated the superior activity of T-DM1 and everolimus in HCC1954 and PDX-derived mouse models. In summary, everolimus in combination with T-DM1 showed strong antitumor effects in HER2-positive breast cancer, both in vitro and in vivo. This effect might be related, at least partially, to mTOR-dependent lysosomal processing of T-DM1, a finding that might apply to other ADCs that require lysosomal processing., Implications: Inhibition of mTOR increases the antitumor activity of T-DM1, supporting that the combination of mTOR inhibitors and antibody-drug conjugates warrants clinical evaluation in patients with HER2-positive breast cancer., (©2022 American Association for Cancer Research.)

Enhancing natural killer (NK) cell-based cancer immunotherapy by overcoming immunosuppression is an area of intensive research. Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFβ-mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic, and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGFβ on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFNγ) while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGFβ1 and CD137 agonist recovered CCL5 and IFNγ secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells. Trastuzumab treatment of fresh breast carcinoma-derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16 + NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFNγ production. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in patients with HER2-positive primary breast cancer, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFNγ production. Our data reveals CD137 as a targetable checkpoint for overturning TGFβ constraints on NK-cell antitumor responses., (©2021 American Association for Cancer Research.)

Advanced bladder cancer is associated with a poor prognosis and limited treatment options. The PI3K/AKT/mTOR pathway is frequently activated in this disease and can be a potential therapeutic target for treatment intervention. We studied the antitumor efficacy of a new targeted therapy, TAK-228 (oral mTORC1/2 inhibitor), in preclinical models of bladder cancer. We evaluated the effects of TAK-228 in combination with a PI3Kα inhibitor (TAK-117) or with chemotherapy (paclitaxel). We used six bladder cancer cell lines and in vivo xenografts models. TAK-228 strongly inhibited cell proliferation in vitro , and reduced tumor growth and angiogenesis in vivo . Three possible biomarkers of response to TAK-228 (basal levels of 4E-BP1, p-4E-BP1/4E-BP1 ratio, or eIF4E/4E-BP1 ratio) were identified. The combination of TAK-228 and TAK-117 had synergistic effects in vitro and in vivo . Furthermore, TAK-228 demonstrated greater efficiency when combined with paclitaxel. TAK-228 also showed ex vivo activity in tumor tissue from patients with treatment-naïve bladder cancer. TAK-228 is a promising investigational agent that induces a strong effect on cell proliferation, tumor growth, and angiogenesis in bladder cancer models. High synergistic effects were observed with TAK-228 combined with a PI3K inhibitor or with chemotherapy. These results are currently being investigated in a clinic trial of TAK-228 plus paclitaxel in patients with metastatic bladder cancer (NCT03745911). IMPLICATIONS: Strong synergistic effects were observed when combining TAK-228 with TAK-117 (a PI3Kα inhibitor) or with paclitaxel chemotherapy. A phase II study at our institution is currently evaluating the efficacy of TAK-228 combined with paclitaxel in patients with metastatic bladder cancer., (©2019 American Association for Cancer Research.)

Natural killer (NK) cells can orchestrate effective antitumor immunity. The presence of tumor-infiltrating NK cells in diagnostic biopsies predicts pathologic complete response (pCR) to HER2-specific therapeutic antibodies in patients with primary breast cancer. Here, we analyzed whether diversity in circulating NK cells might influence tumor infiltration and HER2-specific therapeutic antibody efficacy. We found that numbers of circulating CD57 + NK cells inversely correlated with pCR to HER2-specific antibody treatment in patients with primary breast cancer independently of age, traditional clinicopathologic factors, and CD16A 158F/V genotype. This association was uncoupled from the expression of other NK-cell receptors, the presence of adaptive NK cells, or changes in major T-cell subsets, reminiscent of cytomegalovirus-induced immunomodulation. NK-cell activation against trastuzumab-coated HER2 + breast cancer cells was comparable in patients with high and low proportions of CD57 + NK cells. However, circulating CD57 + NK cells displayed decreased CXCR3 expression and CD16A-induced IL2-dependent proliferation in vitro Presence of CD57 + NK cells was reduced in breast tumor-associated infiltrates as compared with paired peripheral blood samples, suggesting deficient homing, proliferation, and/or survival of NK cells in the tumor niche. Indeed, numbers of circulating CD57 + were inversely related to tumor-infiltrating NK-cell numbers. Our data reveal that NK-cell differentiation influences their antitumor potential and that CD57 + NK cells may be a biomarker useful for tailoring HER2 antibody-based therapeutic strategies in breast cancer., (©2019 American Association for Cancer Research.)