A comprehensive single-cell breast tumor atlas defines cancer epithelial and immune cell heterogeneity and interactions predicting anti-PD-1 therapy response

Abstract

We present an integrated single-cell RNA-seq resource of the breast tumor microenvironment consisting of 236,363 cells from 119 biopsy samples across 8 publicly available datasets. In this computational study, we first leverage this novel resource to define cancer epithelial cell heterogeneity based on two clinically relevant markers and define six new and distinct subsets of natural killer cells. We then illustrate how cancer epithelial cell heterogeneity impacts immune cell interactions. We develop T cell InteractPrint, which considers how cancer epithelial cell heterogeneity shifts the predicted strength of T cell interactions. We use InteractPrint to predict response to immune checkpoint inhibition (ICI) in two clinical trials testing immunotherapy in patients with breast cancer. T cell InteractPrint was predictive in both trials (AUC=0.81 and 0.84), versus PD-L1 expression (AUC=0.54 and 0.72). This result provides an alternative predictive biomarker to PD-L1 to select patients who should receive ICI.

Antibody-drug conjugates in breast cancer: overcoming resistance and boosting immune response

“…While the total number of NK cells was not changed by the STING ADC, the percentage of activated CD69 + NK cells showed a marked increase after therapy, which likely contributed to the antitumor effects. This finding also speaks to the heterogeneity of NK cells within the TME, which has implications in immunotherapy design and clinical practice (56,(91)(92)(93)(94).…”

“…Thus, the development of biomarkers, such as CTCs, to determine the patient population likely to benefit from ADC treatment becomes imperative. To uncover such biomarkers, it is important to conduct studies using advanced analytic techniques of the entire microenvironment, such as single-cell and spatial "omics" and functional assays with tumor organoids and immune cells (109)(110)(111)(112)(113)(114). Understanding how signaling networks change across cell types and how ADCs augment the function of effector immune cells or decrease regulatory immune cells could lead to new biomarker development and therapies.…”

“…The FcγR portion of effector immune cells binds to the Fc portion of antibodies to orchestrate ADCC that kills antibody-coated target cells through the release of perforin and other cytotoxic granules (64). For example, in NK cells, CD16 is one FcγR that, upon binding, phosphorylates immune tyrosinebased activating motifs (ITAMs), leading to NK cell proliferation sy at one moment in time (56). Newer modes of assessing protein include imaging of radiolabeled monoclonal antibody (mAb) by positron emission tomography (PET), termed "immuno-PET."…”

Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations

“…Here we show that isolating organoids without passaging captures both intratumoral heterogeneity and reduces the chance of genetic drift as organoids are generated and used soon after tumor digestion. Given that functional models are lacking in the literature to test the impact of tumor heterogeneity on tumor metastasis [20] and immune interactions [21], this model could be useful for further experimentation.…”