CD137 Costimulation Counteracts TGFβ Inhibition of NK-cell Antitumor Function.

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).

High Numbers of Circulating CD57 NK Cells Associate with Resistance to HER2-Specific Therapeutic Antibodies in HER2 Primary Breast Cancer.

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.

NK Cell Infiltrates and HLA Class I Expression in Primary HER2 Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival.

Purpose: We investigated the value of tumor-infiltrating NK (TI-NK) cells and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer.

Experimental Design: TI-NK cells and HLA-I were determined by IHC in pretreatment tumor biopsies from two cohorts of patients with HER2-positive breast cancer [discovery cohort ( = 42) and validation cohort ( = 71)]. Tumor-infiltrating lymphocytes (TIL) were scored according to international guidelines.

Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications.

The goal of cancer immunotherapy is to establish new or boost pre-existing anticancer immune responses that eradicate malignant cells while generating immunological memory to prevent disease relapse. Over the past few years, immunomodulatory monoclonal antibodies (mAbs) that block co-inhibitory receptors on immune effectors cells - such as cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) - or their ligands - such as CD274 (best known as PD-L1) - have proven very successful in this sense. As a consequence, many of such immune checkpoint blockers (ICBs) have already entered the clinical practice for various oncological indications.

Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy.

Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e.

Targeting NK-cell checkpoints for cancer immunotherapy.

Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity.