The following articles have been recommended for further reading in the field of cancer immunotherapy by Dr. Ignacio Melero, Section Editor of the Immunotherapy Biomarkers section.
“Orchestration of myeloid-derived suppressor cells in the tumor microenvironment by ubiquitous cellular protein TCTP released by tumor cells” by Sho Hangai et al
Cytotoxic therapies may cause immunogenic or immunosuppressive effects in the tumor microenvironment, depending on the cell death pathways induced. Sho Hangai and colleagues provide new mechanistic insight on how necrotic tumor cell-secreted factors may cause immunosuppression via recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor tissue microenvironment. In vitro, translationally controlled tumor protein (TCTP) was identified as a factor highly released by necrotic murine colon cancer cells. TCTP was shown to induce the chemokines CXCL1/2 expression in a paracrine fashion. In vivo, SL4 tumors lacking TCTP had reduced tumor growth and lower levels of CXCL1/2 expression as compared to wild-type tumors. Immune cell infiltrates were also affected, with fewer polymorphonuclear MDSCs (PMN-MDSCs), but not monocytic MDSCs in the TCTP-deficient tumors. They found that the numbers of CD8+ T cells and NK cells were markedly ¡ increased in tumors lacking TCTP and were active in reducing tumor growth, however these cytotoxic cells were not active in wild-type tumors. Altogether, necrotic tumor cell-secreted TCTP induced in monocytic MDSC the expression of CXCL1/2 through toll-like receptor 2 (TLR2), leading to the recruitment of CXCR2-expressing PMN-MDSCs and resulting in an immunosuppressed tumor microenvironment. In samples from human patients with colorectal cancer, TCTP levels were elevated in both serum and tissue and correlated with more advanced disease and worse prognosis.
Why this matters: This study reveals new mechanism of TCTP in contributing to an immunosuppressive tumor microenvironment, which may have implications as a therapeutic target or a biomarker for tumor immune-responsiveness.
“Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models” by Yao-Xin Lin et al
Loss-of-function mutations in the gene that encodes the tumor suppressor protein PTEN are found in many cancers and recent studies have also shown that loss of PTEN protein contributes to an immunosuppressive tumor microenvironment. Using polymeric nanoparticles to locally deliver PTEN mRNA (mPTEN@NP), Yao-Xin Lin and colleagues investigated the effects of partially restoring PTEN tumor cell expression through gene transfer to enhance the efficacy of immune checkpoint blockade. Restoration of PTEN via delivery of mPTEN@NPs resulted in increased apoptosis in prostate (PTEN-Cap8) and melanoma (B16-F10) cancer cell lines, as well as increases in autophagy-related proteins, specifically light chain 3-II (LC3-II) and p62. Further analyses revealed that mPTEN@NP treatment induced immunogenic cell death as a result of autophagy and release of damage-associated molecular patterns (DAMPs) (such as chromatin-associated high-mobility group box 1 (HMGB1), heat-shock proteins, ATP, and calreticulin). In B16-F10 tumor bearing mice, treatment with mPTEN@NPs led to reduced tumor growth and reversal of immunosuppression in the tumor microenvironment, with increased CD8+CD3+ effector T cells and CD4+ T helper cells and decreased Tregs and myeloid-derived suppressor cells. When combined with immune checkpoint blockade, the increased immune cell infiltration and immunogenic cell death-induced tumor reduction effects were amplified. Notably, this approach was also partially successful in an orthotopic prostate cancer model, a cancer that is known to be immunologically ‘cold’.
Why this matters: The results of this study highlight not only the successful methodology of transient gene transfer using polymeric nanoparticles containing mRNA, but also the efficacy of restoring PTEN expression to increase responses to immunotherapies.
“A Burned-Out CD8+ T-cell Subset Expands in the Tumor Microenvironment and Curbs Cancer Immunotherapy” by Miguel F. Sanmamed et al
Understanding the dynamic changes occurring in the tumor microenvironment (TME) is vital to optimizing current immunotherapies and finding additional immunotherapy targets. Through a variety of advanced single-cell and imaging technologies, Miguel F. Sanmamed and colleagues identified granularity in the phenotypes among T cell subsets in the TMEs of non-small cell lung cancer (NSCLC) tumors. Among the most selectively expanded T cell populations increased in the TME compared to non-tumor samples, a proliferative CD8+ T cell population of “burned-out effector” (Ebo) cells was identified based on CyTOF panels and gene expression data. These Ebo cells were characterized by increased expression of checkpoint proteins along with reduced production of interferon-gamma. They were also highly over-activated and proapoptotic. In an immune-proficient patient-derived xenograft mouse model of NSCLC, Ebo cells were increased at 2 weeks post-engraftment, while functional CD8+ effector cell populations decreased with time in the TME. Treatment with avelumab decreased the presence of Ebo cells and prevented the loss of functional effector cells, suggesting a role for the PD-1/PD-L1 axis in the proliferation and maintenance of this dysfunctional T cell population. Analyses of human samples from patients with NSCLC demonstrated that Ebo cells increase with tumor progression. Higher levels of Ebo cells were also associated with non-durable benefits after immune checkpoint blockade, and were independently predictive of poor outcomes.
Why this matters: This study identified a dysfunctional, proliferative, and active yet apoptotic, T cell population distinct from previously described ‘exhausted’ T cells that may be contributing to a poor anti-tumor immune response and could be potentially be targeted for reinvigoration to enhance the efficacy of immune checkpoint blockade.
“Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer” by Surashri Shinde-Jadhav et al
Neutrophil extracellular traps (NETs)—the web-like extracellular protrusions comprised primarily of DNA and globular proteins excreted by polymorphonuclear neutrophils (PMNs) to kill pathogens—have been implicated in autoimmune diseases as well as both pro- and anti-tumor effects in the tumor microenvironment. Surashri Shinde-Jadhav and colleagues investigated the role of NETs in the context of bladder cancer after radiation therapy (RT). Using a syngeneic heterotopic model of invasive urothelial carcinoma, increases in PMNs and NETs were observed after irradiation. Ameliorating NET formation, through genetic models (PAD4-/-) or enzymatic degradation, resulted in reduced tumor growth after RT. Mechanistically, extracellular high mobility group box protein-1 (HMGB1), which has previously shown to contribute to muscle-invasive bladder cancer (MIBC) radioresistance, was required to stimulate PMN NET formation through toll-like receptor 4 (TLR4). When both NETs and extracellular HMGB1 were degraded post-RT, tumor growth was reduced and overall survival of the mice improved. Interestingly, confocal imaging of irradiated tumors revealed that NETs formed a sort of barrier that prevented infiltration of CD8+ T cells, which is postulated to be an immunosuppressive mechanism. An analysis of 104 samples from patients with Muscular invasive bladder cancer (MIBC) pre- and post-RT revealed increased NET formation associated with lack of response to radiotherapy. Patients with non-responsive disease also had higher PMN infiltration pre-and post-RT, and higher post-RT PMN to CD8+ T cell ratios, which was found to be an independent predictor of response.
Why this matters: This paper shows that irradiation of bladder tumors induces the formation of NETs in the tumor microenvironment, which are involved in reducing the density of CD8+ T cell infiltrates. NETs and NET formation could provide actionable targets for cancer immunotherapy as well as measurable biomarker candidates.
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