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Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.

Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141 + DCs and mouse CD103 + DCs, supports anti-tumor immunity by stimulating CD8 + T-cell responses. Here, to understand how cDC1 development changes during tumor progression, we investigated cDC bone marrow progenitors. We found localized breast and pancreatic cancers induce systemic decreases in cDC1s and their progenitors. Mechanistically, tumor-produced granulocyte-stimulating factor downregulates interferon regulatory factor-8 in cDC progenitors, and thus results in reduced cDC1 development. Tumor-induced reductions in cDC1 development impair anti-tumor CD8 + T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development.

Background: Hospitals use time-motion studies to monitor process effectiveness and patient waiting. Manual tracking is labor-intensive and potentially influences system performance. New technology known as indoor positioning systems (IPS) may allow automatic monitoring of patient waiting and progress. The authors tested whether an IPS can track patients through a multistep preoperative process., Methods: The authors used an IPS between October 14, 2005, and June 13, 2006, to track patients in a multistep ambulatory preoperative process: needle localization and excisional biopsy of a breast lesion. The process was distributed across the ambulatory surgery and radiology departments of a large academic hospital. Direct observation of the process was used to develop a workflow template. The authors then developed software to convert the IPS data into usable time-motion data suitable for monitoring process efficiency over time., Results: The authors assigned tags to 306 patients during the study period. Eighty patients never underwent the procedure or never had their tag affixed. One hundred seventy-seven (78%) of the remaining 226 patients successfully matched the workflow template. Process time stamps were automatically extracted from the successful matches, measuring time before radiology (mean +/- SD, 77 +/- 35 min), time in radiology (105 +/- 35 min), and time between radiology and operating room (80 +/- 60 min), which summed to total preoperative time (261 +/- 67 min)., Conclusions: The authors have demonstrated that it is possible to use a combination of IPS technology and sequence alignment pattern matching software to automate the time-motion study of patients in a multidepartment, multistep process with the only day-of-surgery intervention being the application of a tag when the patient arrives.

Occult adenocarcinoma with clinically apparent axillary lymphadenopathy represents a challenging surgical problem. Mammography is frequently unable to identify a primary breast carcinoma, and extramammary sources are common and equally difficult to identify. This may leave the clinician and patient with a conundrum of whether to proceed with "blind" mastectomy. A 35-year-old white female presented with axillary adenopathy and a normal breast physical exam. Mammography was unable to demonstrate a specific tumor. Excisional biopsy of the axillary lymph node demonstrated metastatic adenocarcinoma. Positron emission tomography showed increased uptake in the breast and the axilla, consistent with breast carcinoma and axillary metastases. The patient underwent modified radical mastectomy and pathologic review of the specimen proved infiltrating ductal carcinoma in the breast with metastatic nodes. Positron emission tomography may be helpful in localizing occult carcinoma of the breast that presents with metastatic lymph nodes and in excluding other potential primaries.