The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Commentary/Editorials Section Editor Dr. Christian Capitini.
“T cell-derived interleukin-22 drives the expression of CD155 by cancer cells to suppress NK cell function and promote metastasis” by Daria Briukhovetska et al
Immunity (2023)
IL-22-producing helper (Th) cells are associated with poor prognosis in breast and lung cancer. Daria Briukhovetska et al identified a pathway by which IL-22 binding to its receptor on tumor cells suppresses natural killer (NK) cell activity to promote breast and lung cancer metastasis. Compared to wildtype, mice lacking IL-22 expression experienced lower metastatic spread to the lungs when implanted or intravenously injected with lung or breast cancer cell lines. Increased proportions of IL-22-producing CD4+ T cells localized in metastatic foci of animals injected with tumor cells, and these cells were sufficient to promote lung metastases in tumor-injected animals with homozygous deletions of the locus encoding IL-22. Furthermore, tumor cell-specific deletion of the IL-22 receptor IL-22RA1 or constitutive activation of the IL-22 binding protein resulted in fewer lung metastases. By bulk RNA sequencing, one of the genes with the greatest increase in differential expression in IL-22-stimulated cancer cells was the poliovirus receptor locus, which encodes CD155. Loss of IL-22 was also associated with differential expression of CD226, an NK immunomodulatory cell surface receptor in the lungs. Blockade of CD226 resulted in increased metastases in mice lacking IL-22 as well as impaired NK cell IFNgamma production. Finally, high expression of IL22RA1 corresponded to high expression of PVR and was associated with worse overall survival in cohorts of patients from The Cancer Genome Atlas with lung adenocarcinoma and HER2-positive breast cancer, particularly for stage I and II disease.
Why this matters: This study identifies a new immunosuppressive axis in which IL-22-produced by Th cells promotes metastatic spread and inhibits NK cell immunosurveillance by binding to its receptor on lung and breast cancer cells. IL-22 is neutralized by IL-22 binding protein in murine models and could be developed as a potential therapeutic target in humans.
“Single-cell spatial immune landscapes of primary and metastatic brain tumors” by Elham Karimi et al
Nature (2023)
Historically, brain tumors were largely considered immune-privileged. It is now understood that immune cells do exist in the brain tumor microenvironment (TME), although they are tightly regulated and have unique features distinct to other types of solid tumors. However, limited imaging technologies have not allowed for an accurate profile of the cellular and spatial landscape of the immune TME. Elham Karimi and colleagues assessed multiplexed histology samples via imaging mass cytometry (IMC) to characterize the immune landscape of brain tumors at the single cell level. This technology allowed for detailed assessment of not only the spatial immune landscape of primary and metastatic brain tumors, but also vascular patterns, co-localizing cell types, avoidant cell types, and cellular networks. As expected, a low abundance of T cells were present in the glioblastoma TME, which is largely considered an immune desert. Intriguingly, however, T cell infiltration alone may not be a key driver of prognosis for glioblastoma. Cellular neighborhoods demonstrated that the spatial relationships between infiltrating immune cells were more important than overall abundances in regard to survival. Many of the cellular clusters associated with longer survival included M1-like monocyte-derived macrophages, suggesting that macrophage networks may be prognostic for glioblastoma. Patterns of immune cell co-localization with endothelial cells were also found to be important for tumor cell proliferation in both primary and metastatic brain tumors, underlining the importance of blood-brain barrier integrity and cellular signaling and interactions in the perivascular compartment in brain TMEs.
Why this matters: Immunotherapies have not yet been successful in treating brain tumors. A comprehensive understanding of the immune landscape, both spatially, genotypically, and phenotypically, will be essential to developing therapies that establish durable anti-tumor immunity against brain tumors.
“Enhanced T cell effector activity by targeting the Mediator kinase module” by Katherine A. Freitas et al Science (2022)
A major barrier to immunotherapies based on T cells as the primary mediators of anti-tumor activity is that responses are not always durable due to loss of effector function in T cells via immunosuppression, exhaustion, senescence, and other mechanisms. Using a genome-wide CRISPR screen in CAR T cells, Katherine A. Freitas and colleagues identified the Mediator kinase complex, which functions as a connector between transcriptional enhancers and RNA polymerase II, to be a master regulator of T cell effector function. Targeted deletion of Mediator complex subunit 12 (MED12) and cyclin C (CCNC) increased effector function of CAR and T cell receptor (TCR)-engineered T cells by enhancing proliferation, metabolic fitness, cytokine production, and diminished stemness, even under chronic antigen stimulation. Chromatin immunoprecipitation sequencing revealed that an intact core Mediator complex works to sterically hinder binding of RNA polymerase II and transcriptional activity. As such, MED12 deletion increased core Mediator chromatin occupancy in over 800 genomic regions, including many activators of T cell effector function, such as STAT5 and AP-1 proteins. Moreover, MED12-deficient cells demonstrated increased interluekin-2 sensitivity, further supporting effector function.
Why this matters: A majority of current immunotherapies rely on T cells for the effector and cytotoxic response. This study characterizes an important transcriptional regulatory mechanism involved in T cell effector function, which may be developed into a biomarker or therapeutic target.
“Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity” by Paolo D. A. Vignali et al
Nat Immunol (2023)
Terminally exhausted T (tTex) cells express PD-1 at high levels, yet a predominance of this population among infiltrating lymphocytes also associates with resistance to checkpoint blockade. Using murine models, Paolo D. A. Vignali et al demonstrate that CD8+ tTex cells display a suppressive phenotype akin to Foxp3+ regulatory T cells (Treg), yet uniquely mediated solely through CD39. tTex cells demonstrated similar transcriptional signatures as intratumoral Tregs with equivalent suppression activity to CD4+Foxp3p+Treg cells in ex vivo assays. Strikingly, direct cytotoxicity to target cells was not detected in any suppression experiments, and tTex cells demonstrated suppression even while displaying markedly impaired viability or undergoing apoptosis. Deletion of CD39 or inhibition of downstream adenosine receptors completely abolished immunosuppression mediated by tTex cells. In vivo, inducible CD8-specific deletion of CD39 increased the number of intratumoral T cells, decreased tumor size, and improved therapeutic response to checkpoint blockade. Furthermore, CD39-deficient T cells had improved IFNgamma and IL-2 production and delayed PD-1 and Tim-3 expression, and mitochondrial alteration to reduce tumor hypoxia or treatment with tumor hypoxia-targeting agents lowered the immunosuppressive capabilities of infiltrating CD8+ (but not Foxp3+Treg) T cells.
Why this matters: These data demonstrate a new role for terminally exhausted CD8+ T cells not only as non-contributors to anti-tumor immunity but also as key mediators of immunosuppression in the TME in a CD39-dependent manner. Targeting adenosine signaling in the TME such as via mitigation of hypoxia could overcome this suppressive effect to enhance anti-tumor immunity.