scholarly journals Crosstalk Between the Tumor Microenvironment and Cancer Cells: A Promising Predictive Biomarker for Immune Checkpoint Inhibitors

Author(s):  
Xiaoying Li ◽  
Yueyao Yang ◽  
Qian Huang ◽  
Yu Deng ◽  
Fukun Guo ◽  
...  

Immune checkpoint inhibitors (ICIs) have changed the landscape of cancer treatment and are emerging as promising curative treatments in different type of cancers. However, only a small proportion of patients have benefited from ICIs and there is an urgent need to find robust biomarkers for individualized immunotherapy and to explore the causes of immunotherapy resistance. In this article, we review the roles of immune cells in the tumor microenvironment (TME) and discuss the effects of ICIs on these cell populations. We discuss the potential of the functional interaction between the TME and cancer cells as a predictive biomarker for ICIs. Furthermore, we outline the potential personalized strategies to improve the effectiveness of ICIs with precision.

Author(s):  
Jin G. Jung ◽  
Anne Le

AbstractThe tumor microenvironment (TME) is a complex biological structure surrounding tumor cells and includes blood vessels, immune cells, fibroblasts, adipocytes, and extracellular matrix (ECM) [1, 2]. These heterogeneous surrounding structures provide nutrients, metabolites, and signaling molecules to provide a cancer-friendly environment. The metabolic interplay between immune cells and cancer cells in the TME is a key feature not only for understanding tumor biology but also for discovering cancer cells’ vulnerability. As cancer immunotherapy to treat cancer patients and the use of metabolomics technologies become more and more common [3], the importance of the interplay between cancer cells and immune cells in the TME is emerging with respect to not only cell-to-cell interactions but also metabolic pathways. This interaction between immune cells and cancer cells is a complex and dynamic process in which immune cells act as a determinant factor of cancer cells’ fate and vice versa. In this chapter, we provide an overview of the metabolic interplay between immune cells and cancer cells and discuss the therapeutic opportunities as a result of this interplay in order to define targets for cancer treatment. It is important to understand and identify therapeutic targets that interrupt this cancerpromoting relationship between cancer cells and the surrounding immune cells, allowing for maximum efficacy of immune checkpoint inhibitors as well as other genetic and cellular therapies.


Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2278
Author(s):  
Afshin Derakhshani ◽  
Zeinab Rostami ◽  
Hossein Safarpour ◽  
Mahdi Abdoli Shadbad ◽  
Niloufar Sadat Nourbakhsh ◽  
...  

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.


2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Uqba Khan ◽  
Kaylee Ho ◽  
Eun Kyeong Hwang ◽  
Cristian Peña ◽  
Julianna Brouwer ◽  
...  

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liting Xue ◽  
Xingyuan Gao ◽  
Haoyu Zhang ◽  
Jianxing Tang ◽  
Qian Wang ◽  
...  

Abstract Background Signaling through VEGF/VEGFR induces cancer angiogenesis and affects immune cells. An increasing number of studies have recently focused on combining anti-VEGF/VEGFR agents and immune checkpoint inhibitors (ICIs) to treat cancer in preclinical and clinical settings. BD0801 is a humanized rabbit anti-VEGF monoclonal antibody in the clinical development stage. Methods In this study, the anti-cancer activities of BD0801 and its potential synergistic anti-tumor effects when combined with different immunotherapies were assessed by using in vitro assays and in vivo tumor models. Ex vivo studies were conducted to reveal the possible mechanisms of actions (MOA) underlying the tumor microenvironment modification. Results BD0801 showed more potent antitumor activity than bevacizumab, reflected by stronger blockade of VEGF/VEGFR binding and enhanced inhibitory effects on human umbilical vein endothelial cells (HUVECs). BD0801 exhibited dose-dependent tumor growth inhibitory activities in xenograft and murine syngeneic tumor models. Notably, combining BD0801 with either anti-PD-1 or anti-PD-L1 antibodies showed synergistic antitumor efficacy in both lung and colorectal cancer mouse models. Furthermore, the mechanistic studies suggested that the MOA of the antitumor synergy involves improved tumor vasculature normalization and enhanced T-cell mediated immunity, including increased tumor infiltration of CD8+ and CD4+ T cells and reduced double-positive CD8+PD-1+ T cells. Conclusions These data provide a solid rationale for combining antiangiogenic agents with immunotherapy for cancer treatment and support further clinical development of BD0801 in combination with ICIs.


2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jia-Wei Luo ◽  
Yan-Hua Guo ◽  
Feng-Ying Wu ◽  
Xue-Fei Li ◽  
Xue-Cheng Sun ◽  
...  

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients ( P = 0.0065 ). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.


Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 253-263
Author(s):  
Elisa Giommoni ◽  
Roberta Giorgione ◽  
Agnese Paderi ◽  
Elisa Pellegrini ◽  
Elisabetta Gambale ◽  
...  

Background: To date, no biomarkers are effective in predicting the risk of developing immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitors (ICIs). This study aims to evaluate the association between basal absolute eosinophil count (AEC) and irAEs during treatment with ICIs for solid tumors. Methods: We retrospectively evaluated 168 patients with metastatic melanoma (mM), renal cell carcinoma (mRCC), and non-small cell lung cancer (mNSCLC) receiving ICIs at our medical oncology unit. By combining baseline AEC with other clinical factors, we developed a mathematical model for predicting the risk of irAEs, which we validated in an external cohort of patients. Results: Median baseline AEC was 135/µL and patients were stratified into two groups accordingly; patients with high baseline AEC (>135/µL) were more likely to experience toxicity (p = 0.043) and have a better objective response rate (ORR) (p = 0.003). By constructing a covariance analysis model, it emerged that basal AEC correlated with the risk of irAEs (p < 0.01). Finally, we validated the proposed model in an independent cohort of 43 patients. Conclusions: Baseline AEC could be a predictive biomarker of ICI-related toxicity, as well as of response to treatment. The use of a mathematical model able to predict the risk of developing irAEs could be useful for clinicians for monitoring patients receiving ICIs.


Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1061 ◽  
Author(s):  
Alexandre Perrier ◽  
Audrey Didelot ◽  
Pierre Laurent-Puig ◽  
Hélène Blons ◽  
Simon Garinet

Immune checkpoint inhibitors (ICIs) have demonstrated to be highly efficient in treating solid tumors; however, many patients have limited benefits in terms of response and survival. This rapidly led to the investigation of combination therapies to enhance response rates. Moreover, predictive biomarkers were assessed to better select patients. Although PD-L1 expression remains the only validated marker in clinics, molecular profiling has brought valuable information, showing that the tumor mutation load and microsatellite instability (MSI) status were associated to higher response rates in nearly all cancer types. Moreover, in lung cancer, EGFR and MET mutations, oncogene fusions or STK11 inactivating mutations were associated with low response rates. Cancer progression towards invasive phenotypes that impede immune surveillance relies on complex regulatory networks and cell interactions within the tumor microenvironment. Epigenetic modifications, such as the alteration of histone patterns, chromatin structure, DNA methylation status at specific promoters and changes in microRNA levels, may alter the cell phenotype and reshape the tumor microenvironment, allowing cells to grow and escape from immune surveillance. The objective of this review is to make an update on the identified epigenetic changes that target immune surveillance and, ultimately, ICI responses, such as histone marks, DNA methylation and miR signatures. Translational studies or clinical trials, when available, and potential epigenetic biomarkers will be discussed as perspectives in the context of combination treatment strategies to enhance ICI responses in patients with solid tumors.


Sign in / Sign up

Export Citation Format

Share Document