scholarly journals Spatial drivers and pre-cancer populations collaborate with the microenvironment in untreated and chemo-resistant pancreatic cancer

2021 ◽  
Author(s):  
Daniel Cui Zhou ◽  
Reyka G. Jayasinghe ◽  
John M. Herndon ◽  
Erik Storrs ◽  
Chia-Kuei Mo ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Drug Targets ◽  
Treatment Options ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
List Type ◽  
Treatment Regimens ◽  
Coordinated Expression ◽  
Treatment Naïve

SUMMARYPancreatic Ductal Adenocarcinoma (PDAC) is a lethal disease with limited treatment options and poor survival. We studied 73 samples from 21 patients (7 treatment-naïve and 14 treated with neoadjuvant regimens), analyzing distinct spatial units and performing bulk proteogenomics, single cell sequencing, and cellular imaging. Spatial drivers, including mutant KRAS, SMAD4, and GNAQ, were associated with differential phosphosignaling and metabolic responses compared to wild type. Single cell subtyping discovered 12 of 21 tumors with mixed basal and classical features. Trefoil factor family members were upregulated in classical populations, while the basal populations showed enhanced expression of mesenchymal genes, including VIM and IGTB1. Acinar-ductal metaplasia (ADM) populations, present in 95% of patients, with 46% reduction of driver mutation fractions compared to tumor populations, exhibited suppressive and oncogenic features linked to morphologic states. We identified coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin receptor expression in tumor cells. Higher expression of angiogenic and stress response genes in dendritic cells compared to tumor cells suggests they have a pro-tumorigenic role in remodeling the microenvironment. Treated samples contain a three-fold enrichment of inflammatory CAFs when compared to untreated samples, while other CAF subtypes remain similar. A subset of tumor and/or ADM-specific biomarkers showed differential expression between treatment groups, and several known drug targets displayed potential cross-cell type reactivities. This resolution that spatially defined single cell omics provides reveals the diversity of tumor and microenvironment populations in PDAC. Such understanding may lead to more optimal treatment regimens for patients with this devastating disease.HIGHLIGHTSAcinar-ductal metaplasia (ADM) cells represent a genetic and morphologic transition state between acinar and tumor cells.Inflammatory cancer associated fibroblasts (iCAFs) are a major component of the PDAC TME and are significantly higher in treated samplesReceptor-ligand analysis reveals tumor cell-TME interactions through NECTIN4-TIGITTumor and ADM cell proteogenomics differ between treated and untreated samples, with unique and shared potential drug targets

scholarly journals Synergistic Analysis of Circulating Tumor Cells Reveals Prognostic Signatures in Pilot Study of Treatment-Naïve Metastatic Pancreatic Cancer Patients

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 146
Author(s):  
Sarah Owen ◽  
Emily Prantzalos ◽  
Valerie Gunchick ◽  
Vaibhav Sahai ◽  
Sunitha Nagrath
Keyword(s):  
Pilot Study ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Expression Patterns ◽  
Survival Rates ◽  
Resistance Mechanisms ◽  
Mapk Signaling ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens ◽  
Treatment Naïve

Pancreatic ductal adenocarcinoma is typically diagnosed at late stages and has one of the lowest five-year survival rates of all malignancies. In this pilot study, we identify signatures related to survival and treatment response found in circulating tumor cells (CTCs). Patients with poor survival had increased mutant KRAS expression and deregulation of connected pathways such as PI3K-AKT and MAPK signaling. Further, in a subset of these patients, expression patterns of gemcitabine resistance mechanisms were observed, even prior to initiating treatment. This work highlights the need for identifying patients with these resistance profiles and designing treatment regimens to circumvent these mechanisms.

scholarly journals 894 The bispecific innate cell engagers AFM13 (CD30/CD16A) and AFM24 (EGFR/CD16A) increase the fraction of tumor target-responsive NK cells and boost serial killing

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A938-A938
Author(s):  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Chiara Zambarda ◽  
Karolin Guldevall ◽  
Christian Breunig ◽  
...  
Keyword(s):  
Nk Cells ◽  
Single Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Nk Cell ◽  
Biological Evaluation ◽  
Target Cells ◽  
List Type ◽  
Tumor Target ◽  
Serial Killing

BackgroundThe use of bispecific natural killer (NK) cell engagers has emerged as a successful strategy for immune cell activation and killing of tumor cells through antibody-dependent cellular cytotoxicity (ADCC). Among these, tetravalent, bispecific innate cell engagers (ICE®) with specificity for the activating receptor CD16A selectively triggering innate responses from NK cells or macrophages represent the most clinically advanced concept. The CD30/CD16A specific ICE® AFM13, has shown efficacy in patients with CD30+ lymphomas as monotherapy1 and combination therapy with check-point inhibitors2 and most recently in combination with adoptive NK cell therapy.3 The EGFR/CD16A specific ICE® AFM24, targeting a variety of solid tumors like colorectal, or lung cancer with a unique mode of action independent of EGFR signaling inhibition, is currently evaluated in an ongoing Ph1/2a clinical study.MethodsWe used a microchip-based screening with single cell resolution4 to elucidate the dynamic responses of individual NK cells towards tumor target cells upon treatment with AFM13 or AFM24.ResultsWe found that AFM13 and AFM24 mediated potent activation of NK cells, leading to increased responsive cytotoxic NK cells and significantly increased the number of NK cells that exerted engagement with multiple target cells rendering these NK cells serial killers. Strikingly, bispecific ICE® molecules triggered stronger cytotoxic responses compared to monoclonal antibodies. One suggested strategy to boost killing by NK cells is to use molecular inhibitors or protein constructs that prevent shedding of CD16.5 However, previous results have shown that this can lead to impaired detachment from target cells, reducing the capacity for an individual NK cell to form serial contacts to target cells.6 We observed that the elevated NK cell killing induced by ICE® molecules was largely conserved when cells were treated with the shedding inhibitor Batimastat. Analysis of the functional dynamics of NK cells revealed that inhibition of CD16 shedding prevented NK cell detachment from target cells, resulting in cell cluster formation. This might strongly impact targeting of distant tumor cells by an individual NK cell thus limiting its anti-tumoral activity.ConclusionsIn conclusion, we show that both AFM13 and AFM24 increase the fraction of tumor-target responsive NK cells and boost serial killing of target cells by individual NK cells. Based on these data, ICE® molecules can be characterized as potent anti-tumoral agents leveraging the enormous potential of NK cells while maintaining crucial features of NK cell biology.AcknowledgementsWe thank members of the Önfelt lab for their valuable help and feedback.ReferencesSawas A, Elgedawe H, Vlad G, Lipschitz M, Chen P-H, Rodig SJ, et al. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). Blood 2018;132(Supplement 1):2908–2908.Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, Garcia-Sanz R, et al. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2020. Blood 2020;136(21):2401–2409.Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, Becker-Hapak M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood–derived NK cells facilitates CAR-like responses against CD30 + malignancies. Clin Cancer Res Epub 2021.Guldevall K, Brandt L, Forslund E, Olofsson K, Frisk TW, Olofsson PE, et al. Microchip screening platform for single cell assessment of NK cell cytotoxicity. Front Immunol 2016;7:119.Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013;121(18):3599–608.Srpan K, Ambrose A, Karampatzakis A, Saeed M, Cartwright ANR, Guldevall K, et al. Shedding of CD16 disassembles the NK cell immune synapse and boosts serial engagement of target cells. J Cell Biol 2018;217(9):3267–83.Ethics ApprovalThis work was performed with NK cells from healthy anonymous blood donors, which requires no ethical permit according to local regulations.

scholarly journals Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Wei Lin ◽  
Pawan Noel ◽  
Erkut H. Borazanci ◽  
Jeeyun Lee ◽  
Albert Amini ◽  
...  
Keyword(s):  
Single Cell ◽  
Tumor Cells ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Cellular Composition ◽  
Primary Tumors ◽  
Metastatic Lesions ◽  
Tumor Tissues ◽  
Cell Type Specific ◽  
Different Cell Types

Abstract Background Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues. Methods In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets. Results Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT+ cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival. Conclusions Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.

scholarly journals The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1318
Author(s):  
Scott D. Haller ◽  
Michael L. Monaco ◽  
Karim Essani
Keyword(s):  
United States ◽  
Pancreatic Cancer ◽  
Surgical Resection ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Late Phase ◽  
The United States ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Treatment Regimens

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

Outwitting an Old Neglected Nemesis: A Review on Leveraging Integrated Data-Driven Approaches to Aid in Unraveling of Leishmanicides of Therapeutic Potential

2020 ◽  
Vol 20 (5) ◽  
pp. 349-366 ◽  
Author(s):  
Samuel K. Kwofie ◽  
Emmanuel Broni ◽  
Bismark Dankwa ◽  
Kweku S. Enninful ◽  
Gabriel B. Kwarko ◽  
...  
Keyword(s):  
Drug Targets ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Organometallic Compounds ◽  
Leishmania Species ◽  
Data Driven ◽  
Treatment Regimens ◽  
Inhibitory Potential ◽  
Novel Algorithms ◽  
Almost All

The global prevalence of leishmaniasis has increased with skyrocketed mortality in the past decade. The causative agent of leishmaniasis is Leishmania species, which infects populations in almost all the continents. Prevailing treatment regimens are consistently inefficient with reported side effects, toxicity and drug resistance. This review complements existing ones by discussing the current state of treatment options, therapeutic bottlenecks including chemoresistance and toxicity, as well as drug targets. It further highlights innovative applications of nanotherapeutics-based formulations, inhibitory potential of leishmanicides, anti-microbial peptides and organometallic compounds on leishmanial species. Moreover, it provides essential insights into recent machine learning-based models that have been used to predict novel leishmanicides and also discusses other new models that could be adopted to develop fast, efficient, robust and novel algorithms to aid in unraveling the next generation of anti-leishmanial drugs. A plethora of enriched functional genomic, proteomic, structural biology, high throughput bioassay and drug-related datasets are currently warehoused in both general and leishmania-specific databases. The warehoused datasets are essential inputs for training and testing algorithms to augment the prediction of biotherapeutic entities. In addition, we demonstrate how pharmacoinformatics techniques including ligand-, structure- and pharmacophore-based virtual screening approaches have been utilized to screen ligand libraries against both modeled and experimentally solved 3D structures of essential drug targets. In the era of data-driven decision-making, we believe that highlighting intricately linked topical issues relevant to leishmanial drug discovery offers a one-stop-shop opportunity to decipher critical literature with the potential to unlock implicit breakthroughs.

scholarly journals Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Wang ◽  
Yiyi Liang ◽  
Haiyan Xu ◽  
Xiao Zhang ◽  
Tiebo Mao ◽  
...  
Keyword(s):  
Single Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Single Cell Analysis ◽  
Treatment Options ◽  
Objective Response ◽  
Complete Response ◽  
Ductal Adenocarcinoma

AbstractThe current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.

scholarly journals Novel 3D µtissues Mimicking the Fibrotic Stroma in Pancreatic Cancer to Study Cellular Interactions and Stroma-Modulating Therapeutics

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5006
Author(s):  
Kunal P. Pednekar ◽  
Marcel A. Heinrich ◽  
Joop van Baarlen ◽  
Jai Prakash
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cells ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Collagen Gel ◽  
Current Treatment ◽  
Ductal Adenocarcinoma ◽  
Tumor Type ◽  
Cellular Interactions

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor type with low patient survival due to the low efficacy of current treatment options. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) create a dense fibrotic environment around the tumor cells, preventing therapies from reaching their target. Novel 3D in vitro models are needed that mimic this fibrotic barrier for the development of therapies in a biologically relevant environment. Here, novel PDAC microtissues (µtissues) consisting of pancreatic cancer cell core surrounded by a CAF-laden collagen gel are presented, that is based on the cells own contractility to form a hard-to-penetrate barrier. The contraction of CAFs is demonstrated facilitating the embedding of tumor cells in the center of the µtissue as observed in patients. The µtissues displayed a PDAC-relevant gene expression by comparing their gene profile with transcriptomic patient data. Furthermore, the CAF-dependent proliferation of cancer cells is presented, as well as the suitability of the µtissues to serve as a platform for the screening of CAF-modulating therapies in combination with other (nano)therapies. It is envisioned that these PDAC µtissues can serve as a high-throughput platform for studying cellular interactions in PDAC and for evaluating different treatment strategies in the future.

scholarly journals Interleukin 21 Receptor/Ligand Interaction Is Linked to Disease Progression in Pancreatic Cancer

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1104 ◽  
Author(s):  
Linnebacher ◽  
Mayer ◽  
Marnet ◽  
Bergmann ◽  
Herpel ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Immune Cell ◽  
Xenograft Model ◽  
Receptor Expression ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Ligand Interaction

Pancreatic ductal adenocarcinoma (PDAC) displays a marked fibro-inflammatory microenvironment in which infiltrated immune cells fail to eliminate the tumor cells and often—rather paradoxically—promote tumor progression. Of special interest are tumor-promoting T cells that assume a Th17-like phenotype because their presence in PDAC tissue is associated with a poor prognosis. In that context, the role of IL-21, a major cytokine released by Th17-like cells, was assessed. In all tissue samples (n = 264) IL-21+ immune cells were detected by immunohistochemistry and high density of those cells was associated with poor prognosis. In the majority of patients (221/264), tumor cells expressed the receptor for IL-21 (IL-21R) and also a downstream target of IL-21, Blimp-1 (199/264). Blimp-1 expression closely correlated with IL-21R expression and multivariate analysis revealed that expression of both IL-21R and Blimp-1 was associated with shorter survival time of the patients. In vitro data using pancreatic tumor cells lines provided a possible explanation: IL-21 activated ERK and STAT3 pathways and upregulated Blimp-1. Moreover, IL-21 increased invasion of tumor cell lines in a Blimp-1-dependent manner. As an in vivo correlate, an avian xenograft model was used. Here again Blimp-1 expression was significantly upregulated in IL-21 stimulated tumor cells. In summary, our data showed an association of IL-21+ immune cell infiltration and IL-21 receptor expression in PDAC with poor survival, most likely due to an IL-21-mediated promotion of tumor cell invasion and enhanced colony formation, supporting the notion of the tumor-promoting abilities of the tumor microenvironment.

scholarly journals Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma: A Review of the Current Status of Literature

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 481
Author(s):  
Ashleigh Hull ◽  
Yanrui Li ◽  
Dylan Bartholomeusz ◽  
William Hsieh ◽  
Barry Allen ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Synergistic Effects ◽  
Treatment Options ◽  
Survival Rates ◽  
Current Status ◽  
Ductal Adenocarcinoma ◽  
Physiological Factors ◽  
Tumour Control ◽  
Treatment Regimens ◽  
Clinical Trial Evidence

Pancreatic ductal adenocarcinoma (PDAC) has long been associated with low survival rates. A lack of accurate diagnostic tests and limited treatment options contribute to the poor prognosis of PDAC. Radioimmunotherapy using α- or β-emitting radionuclides has been identified as a potential treatment for PDAC. By harnessing the cytotoxicity of α or β particles, radioimmunotherapy may overcome the anatomic and physiological factors which traditionally make PDAC resistant to most conventional treatments. Appropriate selection of target receptors and the development of selective and cytotoxic radioimmunoconjugates are needed to achieve the desired results of radioimmunotherapy. The aim of this review is to examine the growing preclinical and clinical trial evidence regarding the application of α and β radioimmunotherapy for the treatment of PDAC. A systematic search of MEDLINE® and Scopus databases was performed to identify 34 relevant studies conducted on α or β radioimmunotherapy of PDAC. Preclinical results demonstrated α and β radioimmunotherapy provided effective tumour control. Clinical studies were limited to investigating β radioimmunotherapy only. Phase I and II trials observed disease control rates of 11.2%–57.9%, with synergistic effects noted for combination therapies. Further developments and optimisation of treatment regimens are needed to improve the clinical relevance of α and β radioimmunotherapy in PDAC.

Association of pathological clinical characteristics, PD L 1 receptor expression (sp 142), with tumor lymphocytic infiltration cells (TILs) in patients (pts) with triple negative breast cancer (TNBC) in Tucumán, Argentina.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13049-e13049
Author(s):  
Juan Jose Zarba ◽  
Ana Vinuales ◽  
Silvia Victoria Holgado ◽  
Erika Stagmeyer
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Ductal Carcinoma ◽  
Treatment Options ◽  
Tumor Grade ◽  
Inflammatory Cells ◽  
Lymphocytic Infiltration ◽  
Receptor Expression ◽  
Exact Test ◽  
Immune Pathway

e13049 Background: Breast cancer (BC) is the most prevalent tumor in women and the leading cause of cancer death in women. TNBC has the worst prognosis among BC subtypes and limited treatment options, mainly including chemotherapy. The efficacy of immunotherapy is clear for immunogenic tumors, such as melanoma, kidney cancer, non-lung cancer small cell, among others. BC seems to be less immunogenic. Basal-type TNBC present a prominent infiltration of inflammatory cells, suggesting that an immune pathway plays a role in tumorogenesis. The development of immunotherapy (IO)has reached an important turning point in the history of cancer treatment based on the use of the immune system itself to fight tumor cells. PD-L1 overexpression is the only predictive response biomarker for anti-PD-1 / PD-L1 therapy that is accepted in TNBM. Methods: Retrospectively, 68 cases of TNBC from the Pathological Anatomy Service of the Ntra. Sra. De las Mercedes Maternity Institute, of Tucumán, between 2010 and 2016 were analyzed. VENTANA anti PDL1 sp142 assay platform was used. Tumor-infiltrating immune cells (IC) are scored as the proportion of tumor area that is occupied by PD-L1 staining IC of any intensity. A specimen should be considered to have PD-L1 expression if the specimen exhibits ≥ 1% IC. In addition, carcinomas with a proportion greater than 50% of lymphocytic infiltration and its association with the expression of PD L1 were studied according to the recommendations of the International TILs Working group. Results: The median age of the patients was 56 years (21-80). The predominant histological type was non-specific type ductal carcinoma, reported in 45/68 cases (66%), following the medullar 9 / 68 (13%) lobular in 8/68 (11%), metaplastic 3/68 (4%) and other 4%. The tumor grade (G), half of the cases were G 3 with 34/68 (50%), G 2 with 42%. The largest proportion of pts, 42%, had no lymph node (LN) involvement, 33% had between 1 to 3 positive LN and 25% showed 4 or more LN. Stage II 39/68 patients (58%) in stage III 20/68 (30%), I (9%, 6) and IV (3%, 2). 16% (11/68) of the patients were PD-L1 positive. Tumors with lymphocytic infiltration between 0% and 10% expressed 24% (2/37), no expression was observed in tumors with TIls between 10 and 50% and in cases with lymphocytic infiltration greater than 50% expression of PD L was observed 1 in 9/18 cases (50%) (Fisher's exact test, p < 0.0001). Conclusions: It was demonstrated that there is an association between the stromal lymphocytic infiltrate (TILs) and the expression of PD-L1 in tumor cells, in this population of women from Tucumán, which would help to select patients as candidates for anti PD L1 therapies.

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