scholarly journals Tumor Microenvironment in Breast Cancer—Updates on Therapeutic Implications and Pathologic Assessment

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4233
Author(s):  
Joshua J. Li ◽  
Julia Y. Tsang ◽  
Gary M. Tse
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Treatment Decision ◽  
Tumor Infiltrating Lymphocytes ◽  
Therapeutic Implications ◽  
Cancer Management ◽  
Breast Cancer Management ◽  
Pathologic Assessment ◽  
Infiltrating Lymphocytes

The tumor microenvironment (TME) in breast cancer comprises local factors, cancer cells, immune cells and stromal cells of the local and distant tissues. The interaction between cancer cells and their microenvironment plays important roles in tumor proliferation, propagation and response to therapies. There is increasing research in exploring and manipulating the non-cancerous components of the TME for breast cancer treatment. As the TME is now increasingly recognized as a treatment target, its pathologic assessment has become a critical component of breast cancer management. The latest WHO classification of tumors of the breast listed stromal response pattern/fibrotic focus as a prognostic factor and includes recommendations on the assessment of tumor infiltrating lymphocytes and PD-1/PD-L1 expression, with therapeutic implications. This review dissects the TME of breast cancer, describes pathologic assessment relevant for prognostication and treatment decision, and details therapeutic options that interacts with and/or exploits the TME in breast cancer.

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

scholarly journals Impact of the Tumor Microenvironment on Tumor-Infiltrating Lymphocytes: Focus on Breast Cancer

2017 ◽  
Vol 11 ◽  
pp. 117822341773156 ◽  
Author(s):  
Ivan J Cohen ◽  
Ronald Blasberg
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Immune Checkpoint Blockade ◽  
Physical Barriers ◽  
Infiltrating Lymphocytes

Immunotherapy is revolutionizing cancer care across disciplines. The original success of immune checkpoint blockade in melanoma has already been translated to Food and Drug Administration–approved therapies in a number of other cancers, and a large number of clinical trials are underway in many other disease types, including breast cancer. Here, we review the basic requirements for a successful antitumor immune response, with a focus on the metabolic and physical barriers encountered by lymphocytes entering breast tumors. We also review recent clinical trials of immunotherapy in breast cancer and provide a number of interesting questions that will need to be answered for successful breast cancer immunotherapy.

scholarly journals Panoptic View of Prognostic Models for Personalized Breast Cancer Management

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1325
Author(s):  
Geetanjali Saini ◽  
Karuna Mittal ◽  
Padmashree Rida ◽  
Emiel A. M. Janssen ◽  
Keerthi Gogineni ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Decision ◽  
Prognostic Models ◽  
Disease Stage ◽  
Breast Cancers ◽  
Clinicopathologic Characteristics ◽  
Treatment Decision Making ◽  
Cancer Management ◽  
Breast Cancer Management ◽  
The Individual

The efforts to personalize treatment for patients with breast cancer have led to a focus on the deeper characterization of genotypic and phenotypic heterogeneity among breast cancers. Traditional pathology utilizes microscopy to profile the morphologic features and organizational architecture of tumor tissue for predicting the course of disease, and is the first-line set of guiding tools for customizing treatment decision-making. Currently, clinicians use this information, combined with the disease stage, to predict patient prognosis to some extent. However, tumoral heterogeneity stubbornly persists among patient subgroups delineated by these clinicopathologic characteristics, as currently used methodologies in diagnostic pathology lack the capability to discern deeper genotypic and subtler phenotypic differences among individual patients. Recent advancements in molecular pathology, however, are poised to change this by joining forces with multiple-omics technologies (genomics, transcriptomics, epigenomics, proteomics, and metabolomics) that provide a wealth of data about the precise molecular complement of each patient’s tumor. In addition, these technologies inform the drivers of disease aggressiveness, the determinants of therapeutic response, and new treatment targets in the individual patient. The tumor architecture information can be integrated with the knowledge of the detailed mutational, transcriptional, and proteomic phenotypes of cancer cells within individual tumors to derive a new level of biologic insight that enables powerful, data-driven patient stratification and customization of treatment for each patient, at each stage of the disease. This review summarizes the prognostic and predictive insights provided by commercially available gene expression-based tests and other multivariate or clinical -omics-based prognostic/predictive models currently under development, and proposes a more inclusive multiplatform approach to tackling the challenging heterogeneity of breast cancer to individualize its management. “The future is already here—it’s just not very evenly distributed.”-William Ford Gibson

scholarly journals The prognostic and therapeutic implications of distinct patterns of argininosuccinate synthase 1 (ASS1) and arginase-2 (ARG2) expression by cancer cells and tumor stroma in non-small-cell lung cancer

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alexandra Giatromanolaki ◽  
Adrian L. Harris ◽  
Michael I. Koukourakis
Keyword(s):  
Cancer Cells ◽  
Immune Escape ◽  
Expression Patterns ◽  
Postoperative Outcome ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Stroma ◽  
Cancer Cell Growth ◽  
Therapeutic Implications ◽  
Argininosuccinate Synthase ◽  
Infiltrating Lymphocytes

Abstract Background Arginine (Arg) is essential for cancer cell growth and also for the activation of T cells. Thus, therapies aiming to reduce Arg utilization by cancer may prove detrimental for the immune response. Methods We examined the expression of two major enzymes involved in arginine depletion and replenishment, namely arginase ARG2 and argininosuccinate synthase ASS1, respectively, in a series of 98 NSCLCs. Their association with immune infiltrates and the postoperative outcome were also studied. Results ARG2 was expressed mainly by cancer-associated fibroblasts (CAFs) (58/98 cases; 59.2%), while ASS1 by cancer cells (75/98 cases; 76.5%). ASS1 and ARG2 expression patterns were not related to hypoxia markers. Auxotrophy, implied by the lack of expression of ASS1 in cancer cells, was associated with high angiogenesis (p < 0.02). ASS1 expression by cancer cells was associated with a high density of iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs). ARG2 expression by CAFs was inversely related to the TIL-density and linked with poorer prognosis (p = 0.02). Patients with ASS1 expression by cancer cells had a better prognosis especially when CAFs did not express ARG2 (p = 0.004). Conclusions ARG2 and ASS1 enzymes are extensively expressed in NSCLC stroma and cancer cells, respectively. Auxotrophic tumors have a poor prognosis, potentially by utilizing Arg, thus reducing Arg-dependent TIL anti-tumor activity. ASS1 expression in cancer cells would allow Arg fueling of iNOS+TILs and enhance anti-tumor immunity. However, upregulation of ARG2 in CAFs may divert Arg from TILs, allowing immune escape. Identification of these three distinct phenotypes may be useful in the individualization of Arg-targeting therapies and immunotherapy.

scholarly journals Racial/Ethnic Differences Among Tumor Infiltrating Lymphocytes in Breast Cancer Tumors

2021 ◽  
Author(s):  
Surbhi Bansil ◽  
Anthony Silva ◽  
Alana Taniguchi ◽  
Christina Wiedmer ◽  
Mayumi Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Ethnic Groups ◽  
Ethnic Differences ◽  
Immune Cell ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Racial Ethnic

Abstract PurposeTumor infiltrating lymphocytes (TILs) have emerged as a predictor of cancer treatment response and patient outcomes, including for breast cancer. Current studies investigating racial/ethnic differences in TILs and immune profiles in breast cancer offer varying results. Our study hopes to address the paucity of data in breast cancer tumor microenvironment from different racial/ethnic groups not well represented in the literature.MethodsWe reviewed 183 cases of women diagnosed with early stage breast cancer who received neoadjuvant treatment at two large health systems in Hawaii between 2008 and 2020. We evaluated clinical and demographic information including: age at diagnosis, race/ethnicity, tumor stage, tumor subtype according to ER, PR, and HER2 receptor status and compared them with obtaining a pathologic complete response (pCR) and amount of stromal TILs (sTILs).ResultsWe found a significantly greater amount of sTILs in Asians (37.7%, p=0.01) and Native Hawaiian/Pacific Islander (NHPI) (37.2%, p=0.02) patients compared to White patients on multivariate analysis. We found no significant differences in pCR among the different racial/ethnic groups.ConclusionsRacial/ethnic differences in the amount of sTILs in breast cancer tumors suggest that higher sTIL percentages alone do not predict for pCR. Increases in sTILs in Asian and NHPI patients suggest differences in immune cell profiles in the breast tumor microenvironment. This may in part contribute to known outcome disparities in these populations.

Colon cancer cells acquire immune regulatory molecules from tumor-infiltrating lymphocytes by trogocytosis

2021 ◽  
Vol 118 (48) ◽  
pp. e2110241118
Author(s):  
Jae Hun Shin ◽  
Jaekwang Jeong ◽  
Stephen E. Maher ◽  
Heon-Woo Lee ◽  
Jaechul Lim ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Microenvironment ◽  
Membrane Proteins ◽  
Cancer Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Sequencing Analysis ◽  
Colon Cancer Cells ◽  
Lymphocyte Membrane ◽  
Immunosuppressive Tumor Microenvironment ◽  
Infiltrating Lymphocytes

Cancer cells can develop an immunosuppressive tumor microenvironment to control tumor-infiltrating lymphocytes. The underlying mechanisms still remain unclear. Here, we report that mouse and human colon cancer cells acquire lymphocyte membrane proteins including cellular markers such as CD4 and CD45. We observed cell populations harboring both a tumor-specific marker and CD4 in the tumor microenvironment. Sorted cells from these populations were capable of forming organoids, identifying them as cancer cells. Live imaging analysis revealed that lymphocyte membrane proteins were transferred to cancer cells via trogocytosis. As a result of the transfer in vivo, cancer cells also acquired immune regulatory surface proteins such as CTLA4 and Tim3, which suppress activation of immune cells [T. L. Walunas et al., Immunity 1, 405–413 (1994) and L. Monney et al., Nature 415, 536–541 (2002)]. RNA sequencing analysis of ex vivo–cocultured splenocytes with trogocytic cancer cells showed reductions in Th1 activation and natural killer cell signaling pathways compared with the nontrogocytic control. Cancer cell trogocytosis was confirmed in the patient-derived xenograft models of colorectal cancer and head and neck cancer. These findings suggest that cancer cells utilize membrane proteins expressed in lymphocytes, which in turn contribute to the development of the immunosuppressive tumor microenvironment.

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