The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's co-Section Editor for the Clinical/Translational Cancer Immunotherapy series, Dr. Douglas G. McNeel.
“Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling” by Lauren Brady et al
Nature Communications, 2021, 12:1426
Metastatic prostate cancer typically arises from a single clonal origin but disseminated tumors may accumulate divergent genotypes and phenotypes under therapeutic pressure. Lauren Brady and colleagues used digital spatial profiling to survey intra- and intertumoral heterogeneity across 168 tumor cores punched out of 56 formalin-fixed and paraffin embedded samples collected over an 8-year time interval comprising at least 2 anatomically distinct metastatic sites from 27 patients with treatment-resistant disease. A total of 2,093 unique genes were evaluated for the transcriptomic studies and all 55 markers in the NanoString Human Immuno-Oncology, Drug Target, Activation Status, Cell Typing, and Pan-Tumor panel in addition to androgen receptor and synaptophisin were quantified at the protein level. As expected, substantial inter-tumor heterogeneity was observed across patients. Gene expression profiles and pathway activities between metastases from the same patients were largely concordant, however, for seven patients tumors were classified into different phenotypic categories. For the most part, gene expression was similar between bone and soft tissue metastases. In tumors identified as amphicrine by bulk methods, distinct foci of androgen receptor positive and neuroendocrine negative as well as the inverse case were detected by the spatial profiling. Immune cells were largely absent from tumor cell rich regions and PD-1 as well as CTLA-4 were below the detection limit in most samples. However, high expression of the checkpoint molecules B7-H3 and TIM-3 was detectable in roughly half of the tumors.
“Regulatory T-cell Transciptomic Reprogramming Characterizes Adverse Events by Checkpoint Inhibitors in Solid tumors” by Maria Grigoriou et al
Cancer Immunology Research, 2021, 9:726-734
It is impossible to predict which patients receiving checkpoint inhibitor therapy will experience immune-related adverse events (irAEs), and the mechanisms leading to breakdown of central tolerance are largely unknown. Building on evidence that PD-L1 expression on regulatory T cells (Tregs) can be predictive of response to immunotherapy, Maria Grigoriou et al identify a proinflammatory transcriptional signature in Tregs associated with the development of irAEs across cancer types. CD4+CD25+CD127+ Tregs isolated from the blood of patients with advanced melanoma who developed a broad range of irAEs including hypophysitis, thyroiditis, psoriasis, and colitis after anti-PD-1 treatment revealed significant upregulation of proinflammatory chemokines and cytokines such as CXCL2, CXCL16, CXCL10, and CCR1, while functional and metabolic genes such as CCR3, SERPINE2, ADAM12 and ATP6AP1L were downregulated. Compared to controls from patients that did not experience immune-related toxicity, Tregs from patients that developed irAEs displayed gene expression consistent with an inflammatory-like phenotype with enrichment for interferon alpha and gamma, tumor necrosis factor alpha signaling, and IL-6/JAK/STAT3 signaling, along with metabolic rewiring. The irAE-associated signatures overlapped with those observed in Tregs isolated from the peripheral blood of healthy volunteers with a variety of autoimmune conditions including ulcerative colitis, Crohn’s disease, Hashimoto’s thyroiditis, and rheumatoid arthritis. Expanding the analysis to include patients receiving ICIs for kidney, lung, bladder, and non-small cell lung cancer revealed a similar characteristic irAE-associated signature, defined by a core set of 19 genes primarily involved in inflammatory processes.
“Aryl hydrocarbon receptor signaling controls cd155 expression on macrophages and mediates tumor immunosuppression” by Zachary P McKay et al
Journal of Immunology, 2021, 06:1385-1394
The poliovirus receptor, CD155, is almost universally expressed on solid tumors, but incomplete understanding of its context-dependent immune-stimulatory and suppressive activities have limited therapeutic targeting of this checkpoint. Zachary P McKay et al describe a novel mechanism of immunosuppressive CD155 transcriptional regulation on tumor associated macrophages (TAMs) mediated by the hydrocarbon receptor (AhR). Co-expression of PD-L1 and CD155 on TAMs was observed in specimens from patients with the immunologically cold tumor grade IV malignant glioblastoma. Both lipopolysaccharide (LPS) and IL-4 induced CD155 and PD-L1 on macrophages in vitro, and expression required p38 MAPK or phosphorylated STAT6, respectively, indicating that the checkpoint is upregulated under both classical and alternative activation conditions. Analysis of the upstream region of the CD155 transcriptional start site identified a putative dioxin responsive element. Inhibition of AhR transcription factor activity via either a direct-acting synthetic heterocyclic compound or acceleration of beta-catenin degradation prevented the induction of CD155 under all activation conditions (ie, LPS or IL-4). In a syngeneic immunocompetent murine breast cancer model, AhR inhibition impaired tumor growth and was associated with decreased TAMs along with an elevated CD8+ to regulatory T cell ratio. Strong correlation between markers of AhR expression and CD274 (the locus encoding PD-L1) were seen in The Cancer Genome Atlas glioblastoma cohort in addition to an association between CYP1B1 expression (indicative of sustained AhR activity) and poor survival outcomes.
“Radiotherapy transiently reduces the sensitivity of cancer cells to lymphocyte cytotoxicity” by Karoliina Tuomela et al
Proceedings of the National Academy of Sciences, 2022, 119 (3): e2111900119
Radiation therapy (RT) has well-recognized immunomodulatory effects, which has prompted studies combining RT with immunotherapy. While most research has focused on the effects of RT on cytotoxic T cells, Karoliina Tuomela and colleagues report surprising inhibitory effects of RT on NK cell cytotoxicity. In several solid tumor cell lines—given as hypofractionated high-dose, single high-dose, and fractionated low-dose—NK cell killing was decreased when cells were treated with RT more than 24 hours prior to co-culture but not at more recent timepoints. This resistance to NK cell-induced apoptosis lasted up to 13 days but was diminished at 20 days. Interestingly, while NK cell-tumor cell interactions were unchanged in terms of conjugation and synapse formation, irradiated tumor cells were resistant to perforin, a pore-forming protein necessary for granule-mediated NK cell cytotoxicity. Externalization of phosphatidylserine, which can prevent perforin monomerization for pore formation on the cell surface, coincided with the resistance phenotype. Notably, however, while perforin monomers bound to the surface of irradiated cells, calcium flux was markedly reduced, indicating inhibition of functional pore formation. In vivo, resistance to NK cell-mediated killing for tumor cells exposed to radiation at a time interval of at least 24 hours was confirmed. Immunodeficient mice injected with a 1:1 mixture of tumor cells irradiated at a 24 and 72 hours prior time-point, had significant outgrowth of the tumor cells irradiated at the 72 hour time-point after subsequent injection of peripheral blood human NK cells—mimicking the in vitro time kinetics for the resistance phenotype. Perforin-mediated resistance to T cell granule-mediated cytotoxicity after irradiation was also demonstrated in vitro, expanding the findings to additional lymphocytes across arms of the immune system.
Why this matters: Immunotherapy combined with RT is a highly active area of investigation and understanding all the mechanisms of synergy and antergy between these modalities, and understanding the effects of radiation on immune cells and immune cell function, will be critical for these combinations to be successful.
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