Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

NF2 mutations are known to lead to tumorigenesis in numerous organs, which has generally been attributed to alterations in cell growth signaling pathways. Meng and colleagues suggested a novel role for NF2 in sensing cytoplasmic nucleic acids and mediating antiviral immune defenses. They showed that WT NF2 activated innate immunity via YAP/TAZ inhibition of the protein kinase TBK1, which normally phosphorylates and activates the pivotal interferon regulator IRF3. Clinical NF2 mutants lack this activity, instead exhibiting gain-of-function ability to suppress cGAS-STING signaling, further reducing antitumor immunity. Mechanistically, Meng and colleagues showed that NF2 mutants formed strong associations with IRF3 and TBK1, sequestering them from the cGAS-STING innate immunity machinery in liquid-liquid phase separated condensates. Stimulated by increased levels of cGAMP, activated IRF3 induced condensates via its increased affinity with the mutated FERM domain of the NF2 mutant. Importantly, these condensates could be visualized in patient-derived vestibular schwannomas.Expert Commentary: This work shows that clinically relevant NF2 mutant proteins exhibit gain-of-function activity that results in the suppression of antitumor immunity.Meng F, Yu Z, Zhang D, Chen S, Guan H, Zhou R, et al. Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity. Molecular Cell; Published online August 24, 2021; DOI: 10.1016/j.molcel.2021.07.040.Checkpoint blockade immunotherapy (CBI) mobilizes latent pools of stem-like TCF1+ CD8+ T cells (TSL) rather than reversing the inactivity of terminally differentiated exhausted TCF− CD8+ T cells (TEX), but whether these TSL are maintained in the tumor or at a distant site is not clear. Connolly and colleagues discovered that in patients with lung cancer, TSL were preserved in draining lymph nodes (dLN). Using the NINJA mouse model, they expressed the CD8+ T-cell-recognized GP33 peptide as a neoantigen in the lung. GP33-specific T cells in tumors were constantly differentiating from TSL toward TEX, whereas TSL in DLN were not. The authors identified that tumor and dLN T cells were clonally related, and inhibition of T-cell migration from the dLN to tumors prevented accumulation of TSL in the tumor bed, suggesting that TSL in the dLN provided a continual source of CD8+ T cells that could respond to CBI.Expert Commentary: CBI-responsive, stem-like T cells specific to lung cancers are maintained in draining lymph nodes outside of tumors. Their identification may serve as a response biomarker as well as a T-cell source for immunotherapy.Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, et al. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing anti-tumor immune response. Science Immunology; Published online September 2, 2021; DOI: 10.1126/sciimmunol.abg7836..Reprogramming of macrophages from tumor-promoting to tumorkilling is an attractive therapeutic approach to engage an antitumor immune response. Sun and colleagues show that this can be achieved following treatment of macrophages with monophosphoryl lipid A (MPLA) and IFNγ, which results in induction of iNOS expression and cancer cell killing via activation of cytotoxic T cells. Using mouse models of both breast and ovarian cancer, they showed that combined MLPA and IFNγ treatment suppressed both tumor growth and metastatic outgrowth. This was associated with increased intratumoral infiltration of iNOS expressing macrophages and activated cytotoxic T cells, both of which were required for antitumor activity.Expert Commentary: This study demonstrates effective reprogramming of macrophages with clinically approved agents, warranting further research to explore the clinical applicability of this strategy.Sun L, Kees T, Almeida AS, Liu B, He XY, Ng D, et al. Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell; Published online September 1, 2021; DOI: 10.1016/j.ccell.2021.08.005.The tumor microenvironment (TME) represents an indispensable regulator of tumor growth and progression. Eosinophils are one cell type present in the TME that has been observed to accumulate under different stimuli, but there is limited description of how the function of eosinophils is influenced by TME factors. Using human samples and experimental breast cancer-driven lung metastasis models, Grisaru-Tal and colleagues investigated the relevance of eosinophil accumulation in the lung and their influence on breast cancer metastasis to this site. The metastatic lung actively recruited eosinophils, and both recruited and resident eosinophils were activated by IFNγ and TNFα secreted into the TME. These activated eosinophils further remodeled the TME by stimulating T-cell infiltration, which was required for the antitumorigenic effects of these eosinophils. The authors additionally demonstrated that eosinophils could be activated and subsequently transferred into mice and similarly reduce tumor burden through these mechanisms.Expert Commentary: This study defines the mechanism by which the TME activates eosinophils to combat tumor growth and metastasis and highlights IFNγ and TNFα as potential therapeutic tools to activate eosinophils in breast cancer patients with lung metastases.Grisaru-Tal S, Dulberg S, Beck L, Zhang C, Itan M, Hediyeh-Zadeh S, et al. Metastasis-entrained eosinophils enhance lymphocyte-mediated anti-tumor immunity. Cancer Research; Published OnlineFirst August 24, 2021; DOI: 10.1158/0008-5472.CAN-21-0839.The high incidence of low-grade gliomas in children as opposed to adults suggests that stem or progenitor cells present during development may be susceptible to mutations in key driver genes of gliomagenesis, but the identity of these cells is unclear. To delineate progenitor cells affected upon loss of neurofibromatosis type 1 (Nf1), Jecrois and colleagues generated conditional knockouts of Nf1 using either Pax2-cre to limit expression to the embryonic optic nerve or human hGFAP-cre to limit expression to ventricular zone radial glial stem cells. No abnormality was observed in local PAX2+ progenitors, however, BLBP+ migrating glial progenitors were highly enriched at postnatal day 0.5. These migrating progenitors were absent in the optic nerves of conditional Mek1/2 knockout models, suggesting dependence on Erk/MAPK signaling. Using a novel tracking system, mosaic analysis with double markers, they showed that Nf1−/− migrating glial progenitor cells expanded in the neonatal optic nerve, which initiated tumors. Treatment of neonatal mice with MEK inhibitors through their lactating mother inhibited Erk activation and rescued the enlarged optic nerve size and cellularity.Expert Commentary: In utero administration of low dose MEK inhibition represents a future innovative strategy to abrogate development of optic pathway gliomas.Jecrois ES, Zheng W, Bornhorst M, Li Y, Treisman DM, Muguyo D, et al. Treatment during a developmental window prevents NF1-associated optic pathway gliomas by targeting Erk-dependent migrating glial progenitors. Developmental Cell; Published online August 20, 2021; DOI: 10.1016/j.devcel.2021.08.004.In MAPK pathway-driven melanoma, both immune checkpoint inhibitors (ICI) and MAPK pathway inhibitors are used, however, the optimal sequencing of these agents has not been well defined. Wang and colleagues observed that patients had longer progression-free survival if ICIs were received before MAPK pathway inhibitors and explored the optimal sequence and combinatorial strategy for these drugs in mouse models. A short priming phase with ICIs prior to the combination of ICIs with MAPK pathway inhibitors led to improved inhibition of melanoma brain metastasis. M1-like TAMs and CD8+ T cells were increased with the combination therapy and were necessary as neutralization of these cell populations decreased the efficacy of the ICI priming phase.Expert Commentary: This study suggests that priming tumors with ICIs before beginning combination therapy with ICIs and MAPK inhibitors may overcome resistance, indicating the importance of correctly sequencing therapies to promote the best response in patients.Wang Y, Liu S, Yang Z, Algazi AP, Lomeli SH, Wang Y, et al. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy. Cancer Cell; Published online August 18, 2021; DOI: 10.1016/j.ccell.2021.07.023.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.