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• W3042575428 abstract "Metabolic support for regulatory T (Treg) cells in noninflamed tumors is not well understood. In this issue of Immunity, Kumagai et. al. show how oncogene-driven fatty-acid synthesis favors Treg cells over effector T cells and how this imbalance can be overcome. Metabolic support for regulatory T (Treg) cells in noninflamed tumors is not well understood. In this issue of Immunity, Kumagai et. al. show how oncogene-driven fatty-acid synthesis favors Treg cells over effector T cells and how this imbalance can be overcome. Although oncogenic signaling has long been recognized as a fundamental hallmark of cancer, studies throughout the past two decades have underscored the importance of also establishing a permissive tumor immune microenvironment (TME). This summer marks sixteen years since the discovery that regulatory T (Treg) cells restrain immunity to human cancers (Curiel et al., 2004Curiel T.J. Coukos G. Zou L. Alvarez X. Cheng P. Mottram P. Evdemon-Hogan M. Conejo-Garcia J.R. Zhang L. Burow M. et al.Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.Nat. Med. 2004; 10: 942-949Crossref PubMed Scopus (3765) Google Scholar). In the intervening time, a large body of work has broadened our understanding of Treg cells in cancer immunology (Plitas and Rudensky, 2020Plitas G. Rudensky A.Y. Regulatory T Cells in Cancer.Annual Review of Cancer Biology. 2020; 4: 459-477Crossref Scopus (20) Google Scholar). However, the larger and almost philosophical question of why malignancies so effectively support Treg cell occupancy still lacks a satisfying answer. The explanation, in part, almost certainly lies downstream of oncogenic signaling pathways themselves. Indeed, oncogenic BRAFV600E signaling has been linked to the production of chemokines that preferentially attract Treg cells to the nascent melanoma TME (Shabaneh et al., 2018Shabaneh T.B. Molodtsov A.K. Steinberg S.M. Zhang P. Torres G.M. Mohamed G.A. Boni A. Curiel T.J. Angeles C.V. Turk M.J. Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis.Cancer Res. 2018; 78: 5038-5049Crossref PubMed Scopus (39) Google Scholar). Although human tumors that accumulate Treg cells are broadly seen as “inflamed” specimens that attract effector (Teff) cells equally as well (Spranger et al., 2013Spranger S. Spaapen R.M. Zha Y. Williams J. Meng Y. Ha T.T. Gajewski T.F. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.Sci. Transl. Med. 2013; 5: 200ra116Crossref PubMed Scopus (1063) Google Scholar), some tumors recruit Treg cells without their Teff counterparts (Shabaneh et al., 2018Shabaneh T.B. Molodtsov A.K. Steinberg S.M. Zhang P. Torres G.M. Mohamed G.A. Boni A. Curiel T.J. Angeles C.V. Turk M.J. Oncogenic BRAFV600E Governs Regulatory T-cell Recruitment during Melanoma Tumorigenesis.Cancer Res. 2018; 78: 5038-5049Crossref PubMed Scopus (39) Google Scholar). In this issue of Immunity, Kumagai et al., 2020Kumagai S. Togashi Y. Sakai C. Kawazoe A. Kawazu M. Ueno T. Sato E. Kuwata T. Kinoshita T. Yamamoto M. et al.An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells.Immunity. 2020; 53 (this issue): 187-203Google Scholar broaden our understanding of Treg cell dominance in noninflamed gastric cancers by showing how Treg cell metabolic fitness and Teff cell exclusion are simultaneously controlled downstream of RHOA oncogenic signaling. Based on comprehensive RNA sequencing and flow cytometry analyses of over 100 human gastric-cancer specimens, Kumagai et. al. began their study by revealing a clear association between the presence of RHOA-activating point mutations and the appearance of a particular immunological phenotype: namely, a substantial Treg cell footprint despite an otherwise immunologically cold, noninflamed signature. They found that RHOA-mutated tumors exhibited heightened Treg cell to CD4 and CD8 T cell ratios and that infiltrating Treg cells displayed a CD45RAloFOXP3hiCTLA-4hi effector (eTreg) phenotype. Analysis of gastric-cancer data from The Cancer Genome Atlas confirmed the association between RHOA mutation and a high ratio of FOXP3/CD8 gene expression. This distinct RHOA-associated immune profile was observed in approximately 15% of human gastric cancers and did not correlate with overall tumor mutational burden. These observations stand in contrast to the notion that noninflamed tumors exclude all T cells, by demonstrating a setting wherein Treg cells achieved selective occupancy. However, the underlying mechanisms remained to be defined. The authors first focused on the phenomenon of effector T cell exclusion. Tumor CD8 T cell exclusion has previously been linked to cancer-cell-intrinsic driver mutations through studies involving β-catenin mutation in melanoma. Oncogenic Wnt/β-catenin signaling suppresses tumor production of the chemokine CCL4, in turn attenuating the recruitment of CD103+ dendritic cells (DCs), which were required for T cell priming (Spranger et al., 2015Spranger S. Bao R. Gajewski T.F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity.Nature. 2015; 523: 231-235Crossref PubMed Scopus (1265) Google Scholar). Acknowledging this work, Kumagai et. al. surmise that oncogenic signaling pathways might alternatively impair chemokines that directly attract effector T cells to a tumor. To explore this possibility, they constructed a series of mouse and human gastrointestinal cancer cell lines overexpressing either wild-type RHOA or the oncogenic RHOA Y42C mutant. Analysis of gene expression and protein-secretion levels revealed that RHOA mutation significantly decreased tumor-cell production of CXCL10 and CXCL11—both well-known mediators of Teff cell recruitment in solid tumors. Introduction of the mutation also reduced expression of the chemokine-promoting transcription factor IRF1. Moreover, RHOA-mutated human gastric cancer specimens were found to exhibit reduced levels of CXCL10, CXCL11, and IRF1 in relation to their wild-type counterparts. In contrast, known Treg-recruiting chemokines were not altered by RHOA mutation. To reveal the cell-intrinsic underpinnings of this observation, the authors demonstrated that mutated RHOA decreased phosphorylation of the PTEN tumor suppressor, leading to activation of PI3K-AKT signaling, which suppressed STAT-1 and IRF-1 downstream of GSKβ. Taken together, these results reveal a mechanism whereby oncogenic signaling directly reduces CXCL10 and CXCL11 production to enforce a noninflamed TME. Kumagai et. al. next addressed the mechanism of enhanced Treg cell accumulation. Interestingly, gene set enrichment analysis of RHOA-mutated tumors revealed a transcriptional signature enriched for fatty-acid metabolism. This was consistent with their finding that overexpression of mutant RHOA increased fatty-acid synthase (FAS) and free fatty-acid (FFA) production by tumors. Considering known active PI3K-AKT signaling in RHOA-mutated tumors, studies were performed to demonstrate that FAS (encoded by FASN) was expressed downstream of the PI3K/AKT/mTOR signaling pathway in gastric cancer cells. These results collectively provided an important clue, particularly in light of prior work showing that Treg cells are more reliant on fatty-acid oxidation than their Teff cell counterparts (Michalek et al., 2011Michalek R.D. Gerriets V.A. Jacobs S.R. Macintyre A.N. MacIver N.J. Mason E.F. Sullivan S.A. Nichols A.G. Rathmell J.C. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.J. Immunol. 2011; 186: 3299-3303Crossref PubMed Scopus (1066) Google Scholar). It is now well established that Treg cells engage these metabolic adaptations even within tumors (Plitas and Rudensky, 2020Plitas G. Rudensky A.Y. Regulatory T Cells in Cancer.Annual Review of Cancer Biology. 2020; 4: 459-477Crossref Scopus (20) Google Scholar). It seemed likely that Treg cells could thrive under such metabolic conditions. To close the mechanistic link between oncogene-driven fatty-acid production and Treg cell occupancy in the TME, three convincing studies were performed. First, the murine MC38 colon cancer was transduced with FASN. Indeed, increased fatty-acid synthesis in these tumors resulted in larger numbers of infiltrating Treg cells. As an interesting aside, these tumors also contained reduced numbers of CD8 T cells, suggesting that enforcement of the noninflamed TME was also controlled downstream of FASN. Second, the murine YTN16 gastric cancer was transduced with mutant RHOA. Oncogenic signaling in these tumors resulted in higher numbers of proliferative, non-apoptotic Treg cells, thus linking oncogenic RHOA to Treg cell metabolic fitness. Finally, MC38 tumors were transduced with the RHOA mutation in the presence of shRNA to inhibit FASN expression. As anticipated, this manipulation substantially decreased Treg cell presence in tumors, thereby establishing that Treg cell fitness is a direct result of oncogene-driven fatty-acid production (Figure 1). Of note, one study published very recently offers additional support for this conclusion by showing that expression of the fatty-acid transporter CD36 supports mitochondrial fitness of Treg cells in melanoma and colon cancer microenvironments (Wang et al., 2020Wang H. Franco F. Tsui Y.-C. Xie X. Trefny M.P. Zappasodi R. Mohmood S.R. Fernández-García J. Tsai C.H. Schulze I. et al.CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.Nat. Immunol. 2020; 21: 298-308Crossref PubMed Scopus (81) Google Scholar). Armed with a clear mechanistic understanding of RHOA-enforced tumor immune suppression, Kumagai et. al. explored implications for cancer immunotherapy. Whereas MC38 tumors were normally susceptible to anti-PD-1 treatment, the forced expression of either FASN or oncogenic RHOA conferred considerable resistance. This was closely related to the absence of tumor Ag-specific CD8 T cells, which were only generated by anti-PD-1 treatment in mice bearing wild-type tumors. Moreover, human clinical data were presented to illustrate that a small cohort of RHOA-mutated gastric cancer patients failed to respond to anti-PD-1 therapy. In mice, anti-PD-1 resistance appeared to depend directly on FFA abundance in RHOA-mutated tumors, as RNAi of FASN, or mAb blockade of the fatty-acid scavenger receptor CD36, restored tumor sensitivity. Thus, the finding that anti-PD-1 resistance was oncogene-dependent meant, on the bright side, that it could be rationally targeted. Based on the knowledge that PI3K signaling promotes FASN, mice bearing RHOA-mutated tumors were treated with a small molecule PI3Kβ inhibitor. This drug was selected based on its use in current cancer clinical trials and its inability to directly impair Treg cell function or survival. As expected, treatment with the inhibitor decreased tumor-infiltrating Treg cells, increased CXCL10 and 11, and restored infiltrating CD8 T cells (Figure 1). Moreover, whereas PI3Kβ inhibitor treatment alone did not significantly impair tumor growth, its combination with anti-PD-1 resulted in almost synergistic tumor control, stabilizing tumor growth for >50 days. Although not directly shown, one would surmise that PI3Kβ inhibition recruited PD-1+ T cells into tumors, thereby providing a foothold for anti-PD-1 efficacy. As such, these studies provide strong rationale for combining PI3K inhibitors with anti-PD-1 for RHOA-mutated gastric cancers and for other tumors with similar oncogenic pathway aberrations. This elegant work by Kumagai et. al. is particularly significant in revealing how a single oncogenic driver mutation can govern not one but multiple mechanisms of tumor immune suppression. By defining tumor metabolism as a crucial, integral factor, this study provides an illuminating advance for the field, while revealing a new target for therapeutic intervention. Of note, resistance to targeted inhibitor drugs is a nearly universal problem which can restore tumor immune suppression (Steinberg et al., 2017Steinberg S.M. Shabaneh T.B. Zhang P. Martyanov V. Li Z. Malik B.T. Wood T.A. Boni A. Molodtsov A. Angeles C.V. et al.Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors.Cancer Res. 2017; 77: 1599-1610Crossref PubMed Scopus (46) Google Scholar). Thus, future studies to define how inhibitor drug-resistance pathways govern tumor metabolism and Treg cell occupancy will be needed. Based on findings herein, it will also be of interest to define how oncogene-driven fatty-acid production influences different CD8 Teff cell subsets in tumors, particularly resident memory (TRM) cells, which depend on fatty-acid uptake for their survival (Pan et al., 2017Pan Y. Tian T. Park C.O. Lofftus S.Y. Mei S. Liu X. Luo C. O’Malley J.T. Gehad A. Teague J.E. et al.Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism.Nature. 2017; 543: 252-256Crossref PubMed Scopus (273) Google Scholar). As a growing number of clinical trials combine immune checkpoint blockade with small molecule targeted inhibitors, detailed mechanistic studies, like those shown here, will be of paramount importance in advancing the field. M.J.T. is supported by NIH R01CA225028 , CA214062 , and CA205965 ; the Knights of the York Cross of Honor Philanthropic Fund; and the O. Ross McIntyre, M.D. Endowment. An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T CellsKumagai et al.ImmunityJuly 7, 2020In BriefKumagai et al. find that a subset of gastric cancer (GC) tumors are characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells; these tumors bear mutations in RHOA. RHOA mutations activated the PI3K-AKT-mTOR pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. Full-Text PDF Open Archive" @default.
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• W3042575428 title "Oncogenes Feed Treg Cells without Calling CD8s to the Table" @default.
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