The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC’s Reviews Section Co-Editor, Sandra Demaria, MD.
Tumor-reprogrammed resident T cells resist radiation to control tumors by Ainhoa Arina et al.
T cells are thought to be exquisitely radiosensitive, yet ionizing radiation (IR) has also been shown to promote antitumor T cell immunity in preclinical models. Using longitudinal in vivo imaging of T cell infiltrated tumors, Ainhoa Arina and colleagues reveal functional reprogramming of tumor-resident T cells leading to surprising persistence and anti-cancer activity after focal tumor irradiation. Whole body irradiation caused a dose-dependent loss of circulating and lymphoid CD8+ T cells, but minimal depletion of tumor-resident T cells. Strikingly, tumor-resident T cells isolated after treatment with 20 Gy IR produced higher amounts of interferon gamma than those from non-irradiated tumors. Even though radiation exposure induced similar transcriptional changes (primarily p53 signaling) in both tumor-infiltrating and circulating CD8+ T cells, the gene expression profiles at baseline were markedly different, with intratumoral T cells displaying signatures corresponding to angiogenesis and epithelial-to-mesenchymal transition. Functional analysis revealed TGF-beta as the top upstream regulator of transcriptional changes within the tumor microenvironment, and, indeed, anti-TGF-beta antibody partially re-sensitized tumor-resident T cells to IR. The findings support further studies of rationally designed combination radio- and immunotherapy regimens for the treatment of T cell inflamed tumors.
CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment by Shi Yong Neo et al.
While natural killer cells are thought to primarily exhibit tumoricidal effects, studies have shown that NK cells can acquire regulatory and immune suppressive properties in the context of infection and possibly cancer. Shi Yong Neo and colleagues shed light into how NK cells undergo phenotypic changes within the tumor microenvironment to suppress other infiltrating lymphocyte populations. In two tumor types, breast and sarcoma, tumor-infiltrating NK cells expressed high levels of surface ecto-5’-nucleotidase, CD73, which can inhibit T cell responses through production of adenosine. In co-culture experiments, NK cell expression of CD73 was induced by 4-1BB engagement, and inhibitors of actin polymerization prevented CD73 cell surface localization. At an NK cell to T cell ratio of 1 to 10, CD73+ NK cells significantly reduced CD4+ T cell proliferation in vitro. The CD73+ tumor-infiltrating NK cells expressed known immune checkpoint molecules including LAG-3, VISTA, PD-1 and PD-L1, in addition to upregulating IL-10 and TGF-beta. Treatment with the STAT3 inhibitor GPB730 reduced the production of inhibitory cytokines by CD73+ NK cells, and an anti-IL-10 antibody rescued interferon gamma production by CD4+ T cells in co-culture. Data from the cancer genome atlas revealed a correlation between poor prognosis and high expression of NT5E (which encodes CD73) in breast cancer patients. The findings suggest STAT3 and IL-10 inhibitors could be used in combinations with existing immunotherapies to dampen immunosuppression within the tumor microenvironment.
High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants by Pedram Razavi et al.
Most clinical circulating cell-free DNA (cfDNA) assays target a small panel of genes or known mutation hostpots in order to avoid the identification of large numbers of false positive variants due to high-depth sequencing covering wide genomic regions. To define the technical feasibility of a high-intensity sequencing assay, Pedram Razavi subjected tumor biopsy samples in addition to cfDNA and matched white blood cell genomic DNA from 124 patients with advanced or untreated metastatic breast cancer, non-small cell lung cancer, or castration resistant prostate cancer to targeted capture sequencing comprising 508 genes (2 megabases, greater than 60,000x depth). The assay had high sensitivity, with a per-base error rate ranging from 1x10-5 to 3x10-5, which allowed for the identification of 6 cases with high tumor mutation burden by cfDNA sequencing that were not detected by MSK-IMPACT analysis of tumor biopsies. In the cases defined as hypermutators by cfDNA analysis, mutational signatures were consistent with known mechanisms of genomic instability in the cancer types analyzed, including a characteristic APOBEC mutation signature in breast and colon cancer samples and a smoking-like signature in a lung cancer sample. Notably, only 24.4% of the variants identified in the cfDNA sequencing were detected in matched tumor biopsies. In control patients without cancer, 81.6% of somatic mutations in cfDNA were also detected in white blood cells and 53.3% of mutations detected in patients with non-hypermutator cancers were also white blood cell-matched. Numbers of white blood-cell matched variants correlated with age and gene length in both cancer patients and healthy controls, providing evidence for clonal hematopoiesis as a source for somatic homogeneity. The results support the need for joint analysis of cfDNA and matched white blood cells, and support the notion that a single tumor biopsy does not always capture the full mutational landscape.
Oncolytic viruses engineered to enforce leptin expression reprogram tumor-infiltrating T cell metabolism and promote tumor clearance by Dayana Rivadeneira et al.
Poor infiltration by T cells into tumors and hostile conditions for proliferation and effector function within the tumor microenvironment are major barriers to immune eradication of cancer. To overcome both obstacles, Dayana Rivadeneira et al. engineered an oncolytic Vaccinia virus carrying the adipokine leptin to improve T cell metabolic function within the tumor microenvironment. In mouse models of a non-inflamed melanoma, intratumoral injection of oncolytic Vaccinia virus promoted infiltration of CD8+ T cells with low expression of Tim-3 and PD-1; however, despite the presence of T cells with a “non-exhausted” phenotype, only partial responses were achieved and tumor outgrowth eventually occurred. When tumors were genetically modified to produce leptin (which has been shown to stimulate T cells to increase their oxidative capacity) infiltrating CD8+ T cells were more proliferative in situ and produced elevated levels of interferon-gamma and tumor necrosis factor-alpha after restimulation compared to those in control tumors. Intratumoral injection of leptin-expressing Vaccinia virus led to substantial tumor regressions and complete responses in 27% of treated animals. T cells in tumors responding to the leptin-engineered virus displayed characteristic effector and memory gene expression signatures, and, importantly, upon re-challenge, most of the complete responders rejected the tumors. The study adds to increasing evidence that improving the metabolic function of T cells in the tumor microenvironment could augment therapeutic responses.
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