Cancer Communications最新文献

Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called “cold” tumors which are unresponsive to immunotherapy, and the opposite are “hot” tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of “cold” tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming “cold” tumors into “hot” tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in “cold” tumor.

The cover image is based on the Correspondence Spatial relationship of tertiary lymphoid structures and tumor-associated neutrophils in bladder cancer and prognostic potential for anti-PD-L1 immunotherapy by Xuechun Wang et al., https://doi.org/10.1002/cac2.12491.

Overcoming resistance to immune checkpoint blockade (ICB) therapy will pave the way for effective ICB cancer immunotherapy since a large proportion of cancer patients are not responsive to ICB immunotherapy [1]. The molecular mechanisms of ICB resistance are diverse, including tumor-intrinsic resistant factors (such as genetic and epigenetic disorders), immunosuppressive/disabled factors (such as T cell exhaustion), and environmental restrictive factors (such as neuroendocrine stress and metabolic reprogramming). Deciphering the mechanisms for ICB resistance will provide immense potential for designing new immunotherapeutic strategies in refractory cancers. The tumor microenvironment (TME) includes diverse types of cells, such as immune cells, cancer-associated fibroblasts, and endothelial cells, as well as intercellular cytokines/chemokines, growth factors, and metabolites, which have been recognized as crucial determinants in ICB responsiveness. The recent advent of high-throughput metabolomics and lipidomics analysis reveals that metabolic reprogramming in TME is closely associated with cancer cell invasion, regulated cell death, immune escape, and chemoresistance [2]. On the other hand, immunometabolism also modulates tumor-associated immune cell function and immunotherapy efficacy. For instance, higher expression of major facilitator superfamily domain containing 2A (MFSD2A) in gastric cancer cells inhibits transforming growth factor beta 1 (TGF-β1) production by suppressing cyclooxygenase 2 (COX2)-prostaglandin synthesis, thus promoting antitumor immunity via reprogramming TME [3].

As a major component of lipids in TME, long-chain fatty acids (LCFAs) are important energy supply and cellular membrane components for cancer cells. Indeed, various types of LCFAs have been found in TME, showing different and sometimes opposite influences on tumor progression and antitumor immunity [4]. For example, palmitic acid promotes metastasis in oral carcinomas and melanoma mouse models through stimulating intratumoral Schwann cells and innervation [5], whereas linoleic acid potentiates CD8⁺ T cell antitumor functions via enhancing endoplasmic reticulum-mitochondria contact formation and energetics fitness [6]. Therefore, better understanding of the molecular mechanism for each individual LCFA in tumor immunity is meaningful since it may improve cancer immunotherapy through targeting metabolic reprogramming of TME. In a recent study published in Cell Metabolism, Lai et al. [7] found dietary elaidic acid (EA) supplementation elevates tumoral major histocompatibility complex-1 (MHC-I) expression via acyl-coenzyme A synthetase long chain family member 5 (ACSL5), thus suppressing tumor growth and enhancing anti-programmed cell death protein 1 (anti-PD-1) efficacy (Figure 1).

Acyl-coenzyme A synthetase long-chain family members (ACS

The composition of the extracellular tumor microenvironment (TME) has not been fully delineated, limiting the understanding of general cancer-progressing properties within the cancer niche. The interplay and dynamics between cancer cells and the surrounding structures and cells clearly differ between various subtypes of cancer, adding to the complexity of precision medicine [1].

To better understand the composition and to define the imprinted proteins of the TME in breast cancer and its potential associations with clinical properties of the disease, we performed global proteomic analysis on a cohort of 63 decellularized patient-derived scaffolds (PDSs). PDSs represents the cell-free TME and were prepared using primary lesions from breast cancer patients with available clinicopathological data (Figure 1A, Supplementary file of methods). The PDS method has earlier been shown to maintain tumor tissue heterogeniety in vitro, producing quantitative assessments of the activity of the TME when studying cancer cell lines adapted to various PDS-based cell cultures [2]. Specific gene changes in the cancer population induced by the heterogenous PDS culture conditions have also been linked to clinical observations, validating the selected strategy for this study [2-5].

The analysis of the cell-free PDSs identified 1,844 unique proteins (Supplementary Table S1), showing enrichment for proteins related to metabolism, translation, transport, immunity, and extracellular matrix (ECM). Surprisingly, most proteins were annotated as cytoplasmic, suggesting that intracellular proteins were also associated with the PDSs, as further deliberated below (Supplementary Figure S1). When comparing the protein contents from primary cancer samples with adjacent normal breast tissues, 1,280 of the 1,844 detected proteins from the cell-free compartments were differentially expressed. Normal breast tissues were, in comparison to the PDSs, enriched for proteins involved in oxidation-reducing processes, secretion, regulation of exocytosis, and ECM organization (Supplementary Figure S2).

Next, we used k-means clustering to identify potential subgroups of patients based on the protein composition of the cell-free PDSs. PDS Clusters 1-3 were recognized, distinguished by the expression of proteins in Clusters A-C. Interestingly, the PDS clusters were significantly associated with cancer subtypes (Figure 1B and Supplementary Table S2). Cluster 1 was mainly derived from lobular cancers (63%) and low-grade cancers, showing high levels of 458 proteins involved in ECM organization, biological adhesion, and leukocyte-mediated immunity forming protein Cluster A. Cluster 2 was primarily derived from ductal cancers (77%) and showed pronounced expression of protein Cluster B, comprising of 396 proteins related to exocytosis, secretion and neutrophil degranulation. Cluster 3 included a mixture of ductal and lobular cancers with the highe