Organ development is a complex process governed by the interplay of several signalling pathways that play critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressor PTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR‐29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.

Metabolic, infectious, and tumor cell-intrinsic noxae can all evoke the endoplasmic reticulum (ER) stress response in tumor cells, which is critical for tumor cell growth and cancer progression. Evidence exists that the ER stress response can drive a proinflammatory program in tumor cells and macrophages but, to our knowledge, a role for the tumor ER stress response in influencing macrophages and inflammation in the tumor microenvironment has not been suggested. Here we show that macrophages cultured in conditioned medium from ER-stressed tumor cells become activated, and themselves undergo ER stress with the up-regulation of Grp78, Gadd34, Chop, and Xbp-1 splicing, suggesting a general activation of the ER stress-signaling pathways. Furthermore, these macrophages recapitulate, amplify and expand the proinflammatory response of tumor cells. We term this phenomenon "transmissible" ER stress. Although neither Toll-like receptor (TLR)2 nor interleukin 6 receptor (IL6R) signaling is involved, a reduction was observed in the transmission of ER stress to TLR4 KO macrophages, consistent with the fact that a second signal through TLR4 combined with exposure to tumor ER stress-conditioned medium results in a faster ER stress response and an enhancement of proinflammatory cytokine production in macrophages. The injection of tumor ER stress-conditioned medium into WT mice elicited a generalized ER stress response in the liver. We suggest that transmissible ER stress is a mechanism through which tumor cells can control myeloid cells by directing them toward a proinflammatory phenotype, thus facilitating tumor progression.

Tumor-infiltrating myeloid cells, such as dendritic cells (BMDC), are key regulators of tumor growth. However, the tumor-derived signals polarizing BMDC to a phenotype that subverts cell-mediated anti-tumor immunity have yet to be fully elucidated. Addressing this unresolved problem we show that the tumor unfolded protein response (UPR) can function in a cell-extrinsic manner via the transmission of ER stress (TERS) to BMDC. TERS-imprinted BMDC upregulate the production of pro-inflammatory, tumorigenic cytokines but also the immunosuppressive enzyme arginase. Importantly, they downregulate cross-presentation of high-affinity antigen and fail to effectively cross-prime CD8+ T cells, causing T cell activation without proliferation and similarly dominantly suppress cross-priming by bystander BMDC. Lastly, TERS-imprinted BMDC facilitate tumor growth in vivo with fewer tumor-infiltrating CD8+ T cells. In sum, we demonstrate that tumor-borne ER stress imprints ab initio BMDC to a phenotype that recapitulates several of the inflammatory/suppressive characteristics ascribed to tumor-infiltrating myeloid cells, highlighting the tumor UPR as a critical controller of anti-tumor immunity and a new target for immune modulation in cancer.

Key Points Question Is tumor mutation burden (TMB) associated with improved outcomes of programmed cell death–1 (PD-1)/programmed death ligand–1 (PD-L1) inhibition across PD-L1 expression levels in non–small cell lung cancer (NSCLC)? Findings In this cohort study of 1552 patients with NSCLC, the group with high TMB had improved response rates and survival after receiving PD-1/PD-L1 inhibition therapy across PD-L1 expression subgroups compared with the group with low TMB. High TMB levels were associated with increased CD8-positive T-cell infiltration and distinct immune response gene expression signatures. Meaning These findings suggest that in NSCLC, a high number of nonsynonymous tumor mutations is associated with immune cell infiltration and inflammatory T-cell expression signatures, leading to increased sensitivity to PD-1/PD-L1 inhibition across PD-L1 expression subgroups.

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. Significance: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection. This article is highlighted in the In This Issue feature, p. 1861