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Immune Effector Monocyte–Neutrophil Cooperation Induced by the Primary Tumor Prevents Metastatic Progression of Breast Cancer

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Immune Effector Monocyte–Neutrophil Cooperation Induced by the Primary Tumor Prevents Metastatic Progression of Breast Cancer Immune effector monocyte–neutrophil cooperation induced by the primary tumor prevents metastatic progression of breast cancer Catharina Hagerlinga,b,1,2, Hugo Gonzaleza,3, Kiarash Salaria,3, Chih-Yang Wanga,4, Charlene Lina, Isabella Roblesa, Merel van Gogha, Annika Dejmekc, Karin Jirströmb, and Zena Werba,d,2 aDepartment of Anatomy, University of California, San Francisco, CA 94143-0452; bDepartment of Clinical Sciences, Division of Clinical Oncology and Pathology, Lund University, SE-221 85 Lund, Sweden; cDepartment of Translational Medicine, Lund University, Malmö SUS, SE-214 21 Malmö, Sweden; and dHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143 Contributed by Zena Werb, August 30, 2019 (sent for review May 3, 2019; reviewed by Yves DeClerck and Mikala Egeblad) Metastatic behavior varies significantly among breast cancers. Mech- patients’ breast cancer tumors and is hence an attractive preclinical anisms explaining why the majorityofbreastcancerpatientsnever model to find novel therapeutic alternatives for metastatic breast develop metastatic outgrowth are largely lacking but could underlie cancer (12). We furthermore validated our PDX-derived findings the development of novel immunotherapeutic target molecules. Here with a large primary breast cancer tissue microarray (TMA), pleural we show interplay between nonmetastatic primary breast cancer effusions from breast cancer patients and an immunocompetent and innate immune response, acting together to control metastatic syngeneic mammary cancer model. Taken together, we reveal in- progression. The primary tumor systemically recruits IFNγ-producing terplay between the primary breast cancer tumor and myeloid im- immune effector monocytes to the lung. IFNγ up-regulates Tmem173/ mune response, acting together to control metastatic progression. STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated Results tumor cells in the lungs, preventing metastatic outgrowth. Importantly, Monocyte Recruitment in a Nonmetastatic Model. We studied 3 our findings could underlie the development of immunotherapeu- different triple negative breast cancer PDX lines that in prior tic target molecules that augment the function of immune effector work we found had high (PDX lines HCI-001 and HCI-010) or MEDICAL SCIENCES monocytes and neutrophils. poor (PDX line HCI-002) spontaneous metastatic efficiency (Fig. 1 A and B and SI Appendix, Table S1) (11). Their metastatic metastatic breast cancer | immune effector monocytes | behavior in mice recapitulated patterns similar to those observed in CCR2 | CCL2 | STING the original patients (11, 12). The PDX tumors were transplanted etastatic breast cancer is a major clinical challenge, ac- Significance Mcounting for a discouraging 400,000 deaths per year world- wide (1, 2). Importantly, metastatic behavior varies significantly Metastatic breast cancer is a major clinical challenge, accounting among breast cancers with ∼10 to 15% of breast cancer patients for a discouraging 400,000 deaths per year worldwide. Novel developing distant metastases (3). A wide range of tumor-derived therapeutic alternatives are urgently needed. Cancer immuno- and stromal factors has been showntopromotemetastaticprogres- therapy has proven to be a promising treatment, improving the sion (2, 4). However, although the majority of breast cancer patients survival of patients with cancer; however, currently there are no never develop metastatic breast cancer, it remains to be determined immunotherapies available for advanced breast cancer. Importantly, whether primary breast cancer tumors can actively induce a systemic current cancer immunotherapies primarily target T lymphocytes antimetastatic immune response protecting patients from metastatic rather than myeloid cells, which are critical regulators of metastatic outgrowth, which could potentially provide the backbone for the breast cancer. Novel cancer immunotherapies that directly regulate future development of immunotherapeutic target molecules. the function of various antitumoral myeloid subpopulations in breast Cancer immunotherapy has proven to be a promising treatment, cancer could have therapeutic potential and target metastatic improving the survival of patients with cancer; however, currently breast cancer. there are no immunotherapies available for advanced breast can- cer (5). In fact, the majority of current cancer immunotherapies Author contributions: C.H., H.G., and Z.W. designed research; C.H., H.G., K.S., C.L., I.R., primarily target or augment the function of T lymphocytes rather M.v.G., and A.D. performed research; C.-Y.W. and K.J. contributed new reagents/analytic tools; C.H., H.G., K.S., C.-Y.W., and Z.W. analyzed data; C.H., H.G., and Z.W. wrote the than myeloid cells, which have an important role in innate im- paper; and K.J. made and provided human breast cancer tissue microarrays. munity and are critical regulators of metastatic breast cancer (5, 6). Reviewers: Y.D., University of Southern California; and M.E., Cold Spring Harbor The main myeloid populations involved in metastatic breast cancer Laboratory. are mononuclear monocytes and macrophages, and polymorpho- – The authors declare no competing interest. nuclear neutrophils (7 9). Within each myeloid population there is Published under the PNAS license. a continuum of subpopulations that can have either a pro- or Data deposition: Transcriptome sequence data have been deposited in the Gene Expres- antitumoral phenotype (6, 7). Novel cancer immunotherapies that sion Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE137300). activate and augment the function of antitumoral myeloid sub- 1Present address: Department of Laboratory Medicine, Division of Clinical Genetics, Lund populations could have therapeutic potential and be clinically University, SE-221 85 Lund, Sweden. important for patients with advanced breast cancer. 2To whom correspondence may be addressed. Email: [email protected] or Here we elucidate whether nonmetastatic primary human breast [email protected]. cancer can evoke an antimetastatic myeloid immune response at 3H.G. and K.S. contributed equally to this work. the metastatic site, explaining disparities in the development of 4Present address: Graduate Institute of Cancer Biology and Drug Discovery, College of metastatic breast cancer in patients. We took advantage of the Medical Science and Technology, Taipei Medical University, Taipei 11042, Taiwan. difference in metastatic efficiency between various breast cancer This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. patient-derived xenograft (PDX) lines (10, 11). The PDX model 1073/pnas.1907660116/-/DCSupplemental. harbors bona fide malignancy characteristics directly from the www.pnas.org/cgi/doi/10.1073/pnas.1907660116 PNAS Latest Articles | 1of11 Downloaded by guest on September 30, 2021 orthotopically and allowed to grow to end point (∼20 to 25 mm HCI-010 line from the experiment since HCI-010 tumors grow in diameter) in nonobese diabetic (NOD)/severe combined slower (SI Appendix,Fig.S1A) (12). As expected, we did not detect immunodeficient (SCID) mice, which are deficient in mature T any metastatic foci in lungs of HCI-002 tumor-bearing mice and B cells but can have functionally activated innate immune (transplanted to only 1 side), (Fig. 1D). Intriguingly, compared to cells (13, 14). Accordingly, they provide an appropriate model HCI-001 tumor-bearing mice (transplanted to only 1 side), the to explore the direct impact of innate immune cells in human number of metastatic foci in the lungs of HCI-001/HCI-002 tumor- metastatic breast cancer. bearing mice decreased (Fig. 1D). These findings suggest that the To discern if the differences in the metastatic behavior of the poorly metastatic PDX line HCI-002 evoked a cancer cell- PDXs were independent or dependent upon mechanisms intrinsic independent mechanism that systemically inhibited metastatic to the cancer cells we did a bilateral transplantation experiment breast cancer. (Fig. 1C). We asked if either a highly metastatic or a poorly met- Next, we evaluated the nature of the immune microenviron- astatic PDX line could systemically modulate metastatic efficiency ment in lungs from mice bearing tumors from highly metastatic of the other PDX line. We used the HCI-001 line, which has compared to poorly metastatic PDX lines (Fig. 1E). The 2 highly similarprimarytumorgrowthkineticsasHCI-002butexcludedthe metastatic PDX lines (HCI-001 and HCI-010) induced a significant ABHCI-001 HCI-010 HCI-002 HCI-001 HCI-010 HCI-002 hCD298 mLin C WT 4 wks D 10 E Gating strategy (NOD/SCID) 8 105 6 104 HCI-002 4 * SSC-A 103 2 ** HCI-001 0 # met foci/large lung lobe 0 -103 Orthotopical HCI-001 HCI-001 HCI-002 100 101 102 103 104 105 bi-lateral transplantation HCI-002 bi-lat CD45 5 + low 10 FGMonocytes (CD11b Gr-1 ) Bone marrow ** Lung 4 * 10 *** 103 60 *** cells 6 P=0.057 low ** CD11b 102 cells Gr-1 + + 101 40 4 100 CD11b 0 1 2 3 4 5 + 10 10 10 10 10 10 20 2 Gr-1 among CD45 % of BrdU Percentage of CD45 0 0 2 h 72 h WT HCI-001 HCI-010 HCI-002 Fig. 1. Monocyte recruitment in a nonmetastatic model. (A) Representative flow cytometry plots illustrating disseminated tumor cells (human CD298+ and mouse Lin− [lineage negative for CD31, CD45, and Ter119]) in lungs of HCI-001, HCI-010, and HCI-002 tumor-bearing mice. (B) Hematoxylin and eosin (H&E) staining of lungs show
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